RS20050097A - Acylated,heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals - Google Patents

Abstract

The present invention relates to acylated, heteroaryl-condensed cycloalkenylamines of the formula I, (I) in which A, R1, R2, R3, R4, R5 and n have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds which are useful in the treatment of various disease states including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency. They upregulate the expression of the enzyme endothelial nitric oxide (NO) synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

Description

ACYLATED CYCLOALKENYLAMINES

WITH CONDENSED HETERORAYL AND THEIR

USE AS PHARMACEUTICAL PRODUCTS

This invention relates to fused heteroaryl acylated cycloalkylamines of formula I,

where A, R1, R2, R<3>, R4, R<5> and n have the meanings indicated below. The compounds of formula I are valuable pharmaceutically active compounds useful in the treatment of various disease states, including cardiovascular disorders, such as atherosclerosis, thrombosis, coronary artery disease, hypertension and heart failure. They upregulate the secretion of the enzyme synthase of endothelial nitric oxide (NO), i

they can be used in conditions in which it is desirable to increase the secretion of the mentioned enzyme or increase the content of NO, or normalize the reduced content

NO. This invention also relates to processes for obtaining compounds of formula I, to their use, in particular, as active ingredients in pharmaceutical products and to pharmaceutical preparations containing them.

Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes that "generate nitric oxide (NO) by oxidizing arginine. NO released in the endothelium is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits platelet aggregation, leukocyte adhesion to the endothelium, and intimal smooth muscle cell proliferation.

Endothelial NO synthase is subject to physiological and pathophysiological regulation at both the transcriptional and post-transcriptional levels. The enzyme, when present in the endothelium, can undergo calcium-dependent or calcium-independent activation through phosphorylation of specific amino acids, but also through direct interactions with specific proteins. Stimulators of this, usually transient, release of NO are extracellular arginine, 17p-estrogen and mechanical stimulation by blood flow, which is manifested on the inner surface of the endothelium of blood vessels (shear stress). The latter also leads to the regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research, 1994, 74, 349) were able to obtain a significant increase in eNOS by performing exercise and increasing shear stress associated with it.

Whether the regulation on the post-transcriptional novel is relevant in vivo has not been unequivocally proven. Thus, for example, the administration of a high dose of arginine to patients with coronary heart disease was followed by only a transient improvement in endothelium-dependent vasorelaxation.

On the other hand, the importance of eNOS protein upregulation is accepted in science. Thus, there are findings that show that the protective properties of simvastatin, an HMG-CoA reductase inhibitor, can be attributed, in addition to the lipid-lowering effect, also partially to the increase in eNOSin vivo excretion (Endres et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 8880). In addition, it is known that single point mutations in the 5' wing region of the eNOS gene ("eNOS promoter") and the associated decrease in the rate of transcription of the eNOS gene are associated with an increased risk of coronary spasms in the Japanese population (Nakawama et al., Circulation, 1999, 99, 2864).

Therefore, today it is assumed that the transcriptional and post-transcriptional mechanisms of eNOS regulation are seriously disturbed in a large number of disorders, especially in cardiovascular disorders. Even in the very early stages of a wide variety of cardiovascular disorders, it is possible that dysfunction of this type in the endothelium lining the blood vessels leads to a deficit of bioactive NO, which manifests itself as the progression of the disorder in the form of measurable pathophysiological and morphological strands. Thus, critical steps in early atherogenesis are accelerated by reducing NO release in the endothelium, such as low-density lipoprotein oxidation, monocyte recruitment and deposition in the intimal vessel interior, and intimal cell proliferation. The consequence of atherogenesis is the formation of plaque on the inner part of the blood vessels, which in turn can lead to a reduction in stress shear and a further reduction in the release of endothelial NO and further worsening of the pathology. Since endothelial NO is also a vasodilator, its reduction often also leads to hypertension, which, as an independent risk factor, causes additional organ damage.

Therefore, the goal of the therapeutic approach in treating these disorders must be to interrupt this chain of events, by increasing the secretion of endothelial NO. Experiments with gene transfer, which in vitro led to increased secretion of NO synthase in previously damaged blood vessels, are able to really oppose the described processes, and therefore it is proof of the correctness of such an approach (Varenne et al., Hum. Gene Ther., 2000, 11, 1329).

Some low molecular weight compounds have been described in the literature, which in cell cultures can lead to a direct effect on the transcription and secretion of eNOS. However, the already mentioned statins are only substances that have been shown to increase eNOS in vivo as a side effect. But considering the known range of side effects of this class of substances, it is not clear how far the toxicological effect reaches with unproblematic dosing.

Liao et al. protect in WO 99/47153 and WO 00/03746 the use of rhoGTPase inhibitors and agents that affect the organization of the actin cytoskeleton to increase eNOS in endothelial cells and for the treatment of various disorders, such as, for example, stroke or pulmonary hypertension, but without showing a specific way to achieve the same.

WO 02/064146, WO 02/064545, WO 02/064565 and WO 02/064546 describe benzo-attached acylated cycloalkenylamines that upregulate eNOS secretion in endothelial cells and are useful pharmaceutically active ingredients in the treatment of various diseases, but there is a continuing need for additional eNOS secretion enhancers with favorable properties profile. The present invention meets this need by providing compounds of formula I and methods for their use.

Some acylated cycloalkenylamines fused with an imidazole ring, which bind to the histamine H3 receptor, are useful for example in the treatment of overweight and obesity, and are described in VVO 01/68652. JP 08/325234 describes cycloalkenylamines fused with an imidazole ring, which carry a 2-alkoxy-4-amino-5-halobenzyl substituent on the amino group, and are agonists of the 5-HT-4 receptor and are useful in the treatment of, for example, schizophrenia. EP 1072263 describes nociceptin antagonists useful as analgesics, which include some acylamino-4-hydroxyquinazolin-6-yl)-3,4-dichlorobenzamides, described by Koehler et al., in J. Am. Chem. Soc, 1958, 80, 5779.

The subject of this invention are acylated cycloalkenylamines with a fused heteroaryl of formula I,

in any stereoisomeric forms thereof and mixtures thereof in any ratio, and pharmaceutically acceptable salts thereof, wherein in formula I: ring A containing two carbon atoms in common with ring A and the cycloalkenyl ring of formula I is an aromatic 5-membered or 6-membered ring containing 1 or 2 nitrogen atoms as ring heteroatoms, or an aromatic 5-membered ring containing 1 ring heteroatom, which is an oxygen atom or of sulfur, or 2 heteroatoms in the ring, one of which is a nitrogen atom and the other is an oxygen atom or a sulfur atom; R<1> and R<4> independently of each other, are selected from the group consisting of: H; unsubstituted or at least monosubstituted Ci-Ci0-alkyl, C2-Cio-alkenyl, C2-C10-alkynyl, the substituents of which are selected from the group consisting of F, OH, d-Cs-alkoxy, d-Cs-alkylmercapto, -CN, COOR<6>, CONR<7>R<8> and unsubstituted or at least monosubstituted phenyl and heteroaryl, where the substituents are phenyl and the heteroaryl group is selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3; unsubstituted or at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkoxy and CF3; COR<9>;CONR10R11;COOR<12>; CF3; halogen; -CN; NR<13>R<14>; OR<15>; S(0)mR<16>; SO2NR<17>R<18>and NO2; but they cannot be halogen, -CN or NO2, if R<1> or R<4> are attached to a nitrogen atom in the ring;

R<2> and R<3> independently of each other, are selected from the group consisting of: H; halogen, -CN; unsubstituted or at least monosubstituted Ci-Cio-alkyl, whose substituents are selected from the group consisting of OH, phenyl and heteroaryl; OH; C 1 -C 10 -Alkoxy; phenoxy; S(0)mR<19>;CF3; - CN; N02; C1C10-alkylamino; dKd-C10-alkylamino;

(C 1 -C 6 -alkyl)-CONH-; unsubstituted and at least monosubstituted phenyl-CONH- and phenyl-SO2-0-, whose substituents are selected from the group consisting of halogen, -CN, methyl and methoxy; C1C6-alkyl-SO2-O-; unsubstituted or at least monosubstituted

(C 1 -C 6 -alkyl)-C 0 -, the substituents of which are selected from the group consisting of F, di(C 1 -C 3 -alkyl)amino, pyrrolidinyl and piperidinyl; and phenyl-CO-, where the phenyl part is unsubstituted or at least monosubstituted with substituents selected from the group consisting of C1-C3-alkyl, halogen and methoxy; but they cannot be halogen, -CN or NO2, if R<2> and R<3> are attached to a nitrogen atom in the ring;

where

if A represents a 6-membered aromatic ring, 2 or 3 groups R<1>, R2R<3> and R<4> present are attached to carbon atoms in the A ring, which are not shared with a cycloalkenyl ring, and if A is a 5-membered aromatic ring, 1, 2 or 3 groups R<1>, R2, R<3> and R<4> are present, which are attached to carbon atoms in the A ring, which are not shared with cycloalkenyl ring, and in the case of a pyrrole, pyrazole or imidazole ring, for nitrogen atom 1 in the ring;

R<5> is an Ar or Hetar group, both unsubstituted or bearing one or more identical or different substituents selected from the group consisting of: halogen; -CN; NH2; unsubstituted or at least monosubstituted Ci-Cio-alkyl, C2-Cio-alkenyl, C2-C10-alkynyl, Ci-Cio-alkoxy, Ci-Cio-alkylamino and di(Ci-Cio-alkyl)amino, whose substituents are also selected from the group consisting of F, OH, Ci-Cs-alkoxy, aryloxy, Ci-Cs-alkylmercapto, NH2, Ci-Cs-alkylamino and di(C1C8-allyl)amino; C3-C5-alkanediyl; phenyl; heteroaryl; C 4 -alkyl substituted with aryl or substituted with heteroaryl; CF3; N02; OH; phenoxy; benzyloxy; (C 1 -C 10 -alkyl)-COO-; SCOJmR<20>; SH; phenylamino; benzylamino; (C1-C10-alkyl)-CONH-; (C1-C10-alkyl)-CO-N(C1-C4-alkyl)-; phenyl-CONH-; phenyl-CO-N(C1-C4-alkyl)-; heteroaryl-CONH-; heteroaryl-CO-N(C1-C4-alkyl)-; (C 1 -C 10 -alkyl)-CO-; phenyl-CO-; heteroaryl-CO-; CF3-CO-; -OCH20-; -OCF20-; -OCH2CH20-; -CH2CH20-; COOR<21>; CONR<22>R<23>;C(NH)-NH2; S02NR24R2<5>; R26SO2NH-; R<27>SO2N(C1C6-alkyl)-; and the residue of a saturated or at least monosaturated aliphatic, monocyclic 5-membered to 7-membered heterocycle, containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, the heterocycle which may be substituted with one or more substituents selected from the group consisting of halogen, C1C3-alkyl, C1C3-Alkoxy, OH, oxo and CF3, where said heterocycle can optionally be fused with said Ar group or said Hetar group; where all aryl, heteroaryl, phenyl, aryl-containing groups, heteroaryl-containing groups and phenyl-containing groups, which are optionally present in said substituents of said Ar group or said Hetar group, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, Ci-C3-alkyl, OH, Ci-C3-Alkoxy and CF3;

R<6> is selected from the group consisting of: H; C 1 -C 6 -alkyl, which may be substituted with one or more substituents selected from the group consisting of F, C 1 -C 8 -alkoxy and di(C 1 -C 8 -alkyl)amino; aryl-(Ci-C4-alkyl)- and heteroaryl-(Ci-C4-alkyl)-, both of which may be substituted with one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and di(C1-C6-alkyl)amino;

R<7> is selected from the group consisting of: H; C 1 -C 8 -alkyl, which may be substituted with one or more substituents selected from the group consisting of F, C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino and phenyl; phenyl; indanyl and heteroaryl; where each of these aromatic groups may be unsubstituted or bear one or more substituents selected from the group consisting of halogen, -CN, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and CF 3 ;

R<8> is H or C1-C6-alkyl;

R<9> is selected from the group consisting of: C1-C10-alkyl which may be substituted with one or more substituents from the group consisting of F, C1-C4-alkoxy and di(C1-C3-alkyl)amino; and unsubstituted or at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of Ci-C3-alkyl, Ci-C3-alkoxy, halogen, -CN and CF3;

R<10> independently of R<7>, is defined as R<7>;

R<11> independently of R<8>, is defined as R<8>;

R<12> independently of R<6>, is defined as R<6>;

R<13> is selected from the group consisting of: H; C 1 -C 6 -alkyl; unsubstituted or substituted phenyl, benzyl, heteroaryl, (CrC6-alkyl)-CO-, phenyl-CO- and heteroaryl-CO-, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, d-C3-alkoxy and CF3; where one or more of these substituents may be present;

R<14> independently of R<13>, is defined as R<13>;

R<15> is selected from the group consisting of: H; C 1 -C 10 -alkyl; (Ci-C3-Alkoxy)-Ci-C3-alkyl- and substituted and unsubstituted benzyl, phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, Ci-C3-alkyl, Ci-C3-Alkoxy and CF3; where one or more of these substituents may be present;

R16 is also selected from the group consisting of: Ci-C8-alkyl, which can be substituted with one or more substituents selected from the group consisting of F, OH, Ci-C8-alkoxy, aryloxy, Ci-C8-alkylmercapto, Ci-C8-alkylamino and di(C1-C8-alkyl)amino; CF3i substituted or unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3; where one or more of these substituents may be present;

R<17> independently of R7 is defined as R<7>;

R<18> independently of R<8>, is defined as R<8>;

R19 independently of R<16>, is defined as R<16>;

R<20> independently of R<16>, is defined as R<16>;

R<21> independently of R<6>, is defined as R<6>;

R<22> independently of R<7>, is defined as R<7>;

R<23> independently of R<8>, is defined as R<8>;

R<24> independently of R<7>, is defined as R<7>;

R<25> independently of R<8>, is defined as R<8>;

R26 independently of R<16> is defined as R<16>;

R<27> independently of R<16>, is defined as R<16>;

heteroaryl is a 5-membered to 10-membered aromatic, monocyclic or bicyclic heterocycle residue containing one or more heteroatoms selected from the group consisting of N, O and S;

A heter group is the residue of a 5-membered to 10-membered, aromatic, monocyclic or bicyclic heterocycle containing one or more heteroatoms selected from the group consisting of N, O and S;

aryl is phenyl, naphth-1-yl or naphth-2-yl;

The Ar group is phenyl, naphth-1-yl or naphth-2-yl;

m is 0, 1 or 2;

n is 1, 2 or 3;

under the condition,

to exclude compounds with the formulas:

in which R<50> is selected from: hydrogen, unsubstituted C1-C6-alkyl, C1-C6-alkoxy, unsubstituted C1-C6-alkylthio, halogen, -CN, CF3, OH, amino, C1-C6-alkylamino and di(C1-C6-alkyl)amino;

and conclude compounds with formulas:

in which R<5>1, R52, R53 and R54 are selected from: hydrogen, unsubstituted or hydroxy-substituted C-1-C6-alkyl, halogen, amino, C1-C6-alkylamino and di(C1-C6-alkyl)amino, and R55 is unsubstituted or substituted phenyl, thienyl, furyl, pyrrolyl or oxazolyl; and the compound: N-(2-amino-5,6,7,8-tetrahydro-4-hydroxyquinazolin-6-yl)-3,4-dichlorobenzamide is excluded.

If groups or substituents in the compounds of formula I, such as for example aryl, heteroaryl, alkyl, etc., can be present several times, all of them, independently of each other, have the indicated meanings, and therefore can be identical or different from each other in each individual case. As an example, the group di(C1-C10-alkyl)amino can be mentioned, where the substituents can be identical or different. When a group in the compounds of formula I can be at least monosubstituted, or when it bears one or more substituents, it can be substituted, for example, with one, two, three, four or five substituents. When a group is substituted by two or more substituents, these substituents can be identical or different from each other.

Alkyl, alkenyl and alkynyl radicals can be linear or branched, acyclic or cyclic. This is also true when they are part of other groups, for example alkoxy groups, alkoxycarbonyl groups or substituted amino groups, or when they are substituted.

Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, n-isomers of these residues, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl. The term alkyl herein expressly includes cycloalkyl groups and cycloalkyl-alkyl groups, i.e. alkyl substituted with cycloalkyl, groups containing at least three carbon atoms. Examples of such cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. All cycloalkyl groups can be substituted with one or more, identical or different Ci-C4-alkyl residues, especially with methyl. Examples of substituted cycloalkyl radicals are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl. In addition, unless otherwise indicated, the term alkyl herein includes also unsubstituted alkyl radicals, as well as alkyl radicals substituted with one or more, for example 1, 2, 3 or 4, identical or different radicals, for example aryl groups. In substituted alkyl moieties, for example, arylalkyl-, hydroxyalkyl-, such as hydroxy-(C 1 -C 4 )-alkyl-, or alkoxyalkyl-, such as C 1 -C 4 -alkyl-O-(C 1 -C 3 )-alkyl-, these substituents may be present in any desired position.

Examples of alkenyl and alkynyl groups are vinyl, 1-propenyl, 2-propenyl, i.e. allyl, 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, ethynyl, 2-propynyl, i.e. propargyl, 2-butynyl or 3-butynyl. The term alkenyl here specifically refers to cycloalkenyl groups and cycloalkenyl-alkyl groups, i.e. alkyl substituted with cycloalkenyl, groups containing at least three carbon atoms. Examples of cycloalkenyl radicals are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. All cycloalkenyl groups can be substituted with one or more, identical or different C 1 -C 4 -alkyl residues, especially with methyl. In addition, unless otherwise indicated, the terms alkenyl and alkynyl herein also include unsubstituted alkenyl and alkynyl moieties, as well as alkenyl and alkynyl moieties substituted with one or more, for example 1, 2, 3 or 4 identical or different moieties, for example aryl groups. In substituted alkenyl and alkynyl moieties, for example arylalkenyl-, hydroxyalkenyl-, such as hydroxy-(C2-C3)-alkenyl-, or alkoxyalkenyl-, such as C1-C3-alkyl-O-(C2-C4-alkenyl)-, the substituents may be present in any desired position.

Examples of Cs-Cs-alkanediyl are -CH2CH2CH2-, -CHrCH(CH3)-, -CH2CH2CH2CH2- and

-CH2CH2CH2CH2CH2- groups.

Unless otherwise indicated, the aforementioned phenyl residues, naphthyl and indanyl residues and heterocyclic residues (including heteroaryl residues), may be unsubstituted or may bear one or more, for example 1, 2, 3 or 4 substituents, indicated in the above definition, and these substituents may be present in any desired position. If nitro groups are present as substituents in the compounds of formula I, in a preferred embodiment of this invention, up to two nitro groups are present in the molecule. With monosubstituted phenyl residues, the substituent can be in position 2, position 3 or in position 4, and with disubstituted phenyl residues, the substituents can be in positions 2,3-, positions 2,4-, positions 2,5-, positions 2,6-, positions 3,4- or positions 3,5-. In the case of trisubstituted phenyl residues, the substituents may be in the 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. In case of four-fold substituted phenyl residues, the substituents can be in positions 2,3,4,5-positions 2,3,4,6 or in positions 2,3,5,6. Tolyl (ie methylphenyl) can be 2-tolyl, 3-tolyl or 4-tolyl. Naphthyl can be 1-naphthyl or 2-naphthyl. For monosubstituted 1-naphthyl residues, the substituent can be in position 2, position 3, position 4, position 5, position 6, position 7 or position 8, and for monosubstituted 2-naphthyl residues, in position 1, in position 3, position 4, position 5, position 6, position 7 or position 8. For more substituted naphthyl residues, for example, 1-naphthyl residues or 2-naphthyl residues, which carry two or three substituents, these substituents can be present in any desired position. Indanyl residues are indan-1-yl residues and indan-2-yl residues, which may be unsubstituted or bear one or more of the indicated substituents. In the case where the indanyl residues are substituted, the substituent or substituents may be genuine in any of the possible positions.

Unless otherwise stated, heteroaryl radicals and heterocyclic radicals are preferably derived from heterocycles containing 1, 2, 3 or 4 heteroatoms, which may be identical or different; they are preferably derived from heterocycles containing 1, 2 or 3, and especially 1 or 2, heteroatoms which may be identical or different. Unless otherwise stated, these heterocycles may be monocyclic or polycyclic, for example, monocyclic, bicyclic or tricyclic. It is preferable that they are monocyclic or bicyclic. Preferably, the number of members in the ring is 5, 6, 8, 9, or 10. Preferably, the individual rings are 5-membered rings, 6-membered rings, or 7-membered rings. Examples of monocyclic and bicyclic heterocyclic systems from which the residues found in the compounds of formula I can be derived are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole (i.e. oxazole), 1,2-oxazole (i.e. isoxazole), 1,3-thiazole (i.e. thiazole), 1,2-thiazole (ie, isothiazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, 1,4-dioxin, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,2-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine, 1,3-thiazepine, indole, benzothiophene, benzofuran, benzothiazole, benzoxazole, benzimidazole, benzodioxole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, thienothiophenes, 1,8-Naphthyridine and other naphthyridines, pteridine or phenothiazine, each in a saturated form (ie perhydro form), or partially unsaturated form, for example, in dihydro form or tetrahydro form, or in maximally unsaturated form, or aromatic form, provided that the respective forms are known and stable. The term "aryl" and the term "heteroaryl" as used herein include bicyclic moieties in which both rings are aromatic, as well as bicyclic moieties in which only one ring is aromatic. The same applies to the name "Ar Group" and the name "Hetar Group". Suitable heterocycles are, for example, saturated heterocycles: pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine. The degree of saturation of heterocyclic groups is indicated in their individual definitions. Unsaturated heterocycles may contain, for example, 1, 2 or 3 double bonds within the ring system. In particular, 5-membered and 6-membered rings can also be aromatic.

Residues derived from said heterocycles can be attached via any suitable carbon atom. Residues derived from nitrogen heterocycles, which may carry a hydrogen atom or a substituent on a ring nitrogen atom, such as a pyrrole, imidazole, pyrrolidine, morpholine or piperazine residue, may also be connected via a ring nitrogen atom, especially if the respective heterocyclic residue is connected to a carbon atom. For example, a thienyl residue can be present as a 2-thienyl residue, or a 3-thienyl residue, a furyl residue as a 2-furyl residue or a 3-furyl residue, a pyridinyl residue as a 2-pyridinyl residue, a 3-pyridinyl residue or a 4-pyridinyl residue, a piperidinyl residue as a 1-piperidinyl residue (ie piperidino residue), a 2-piperidinyl residue, a 3-piperidinyl residue, or a 4-piperidinyl residue. (thio)morpholinyl residue as 2-(thio)morpholinyl residue, 3-(thio)-morpholinyl residue or 4-(thio)morpholinyl residue (ie thiomorpholino residue). A residue derived from 1,3-thiazole or imidazole, which is attached via a carbon atom, may be attached via the 2-position, the 4-position, or the 5-position.

In the case where the heterocyclic groups are substituted, they may bear one or more, for example, 1, 2, 3 or 4, identical or different substituents. Substituents in the heterocycles may be present in any desired position, for example, in the 2-thienyl residue or in the 2-furyl residue in position 3, and/or position 4, and/or position 5, in the 3-thienyl residue or 3-furyl residue in position 2, and/or position 4, and/or position 5, in the 2-pyridinyl residue in position 3, and/or position 4, and/or 5, and/or position 6, in the 3-pyridinyl residue in position 2, and/or position 4, and/or position 5, and/or position 6, in the 4-pyridinyl residue in position 2, and/or position 3, and/or position 5, and/or position 6. Suitable nitrogen heterocycles may also be present as N-oxides or quaternary salts, containing a counterion, derived from a pharmaceutically acceptable acid. For example, pyridine residues may thus be present as pyridine-N-oxides.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

This invention encompasses all stereoisomeric forms of the compounds of formula I. The centers of asymmetry present in the compounds of formula I, all independently of each other, may have an S configuration or an R configuration. This invention encompasses all possible enantiomers and diastereomers, and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and/or diastereomers, in all ratios. Thus, the compounds of this invention, which may exist as enantiomers, may be present in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In terms of cis/trans isomerism, this invention includes both the cis form and the trans form, as well as mixtures of these two forms in all ratios. All these forms are the subject of this invention. Obtaining the individual stereoisomers can be done, if desired, by separating the mixture by conventional methods, for example, chromatography or crystallization, using stereochemically uniform starting materials for the synthesis, or by stereoselective synthesis. Optionally, derivatization can be performed prior to separation of stereoisomers. The separation of the mixture of stereoisomers can be done in the phase of the compound of formula I, or in the phase of an intermediate during the synthesis, or in the phase of the starting compound. The present invention also encompasses all tautomeric forms of the compounds of formula I.

In case the compounds of formula I contain more acidic or basic groups, this invention also covers their corresponding pharmaceutically or toxicologically acceptable salts, and especially their pharmaceutically usable salts. Thus, the compounds of formula I, which contain acidic groups, can be represented by salts on these groups and can be used in accordance with the present invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia and organic amines, such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula I, which contain one or more basic groups, i.e. groups that can be protonated, can be crucial and can be used in accordance with the present invention as their addition salts with inorganic or organic acids. Examples of suitable acids are hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid and p-toluenesulfonic acid, naphthalene-disulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, chilibamic acid, pimelic acid, maleic acid. acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids, which are known to a person skilled in the art. If the compounds of formula I simultaneously contain acidic and basic groups in the molecule, this invention also includes, in addition to the mentioned salt forms, internal salts or betaines (zwitterions). Salts of a compound of formula I can be obtained by conventional methods known to a person skilled in the art, for example, by contacting a compound of formula I with an organic or inorganic acid, or base, in a solvent or diluent, or from other salts, by anion exchange or cation exchange. This invention also includes all salts of compounds of formula I which, due to their low physiological compatibility, are not directly usable as pharmaceutical products, but which can be used, for example, as intermediates in chemical reactions, or to obtain pharmaceutically acceptable salts.

This invention also includes all solvates of compounds of formula I, for example hydrates and adducts with alcohols, active metabolites of compounds of formula I, and also derivatives and prodrugs of compounds of formula I, which contain physiologically tolerable and leaving groups, for example esters, amides and compounds in which the N-H group indicated in formula I is replaced by an N-alkyl group, such as N-methyl, or by an N-acyl group, such as N-acetyl or N-argininyl, including pharmaceutically acceptable salts formed on the functional groups present in the N-acyl group.

In preferred embodiments of the present invention, one or more structural residues in the compounds of formula I, including number n, A ring, substituents R<1> to R<5>, and other groups present in the compounds of formula I, independently of each other, have the following preferred meanings, more preferred meanings, even more preferred meanings, or most preferred meanings.

In a preferred embodiment of the present invention, the 5-membered or 6-membered monocyclic A ring having two carbon atoms in common with the cycloalkenyl ring of formula I is preferably selected from the following rings:

In the above and below formulas of the specific A rings, the upper of the two free bonds is directed toward the CH2 group in the fused cycloalkenyl ring of formula I, and the lower of the two free bonds is directed toward the (CH2)n group in formula I.

In the next preferred embodiment of this invention, the A ring is an aromatic 6-membered ring containing 1 or 2 nitrogen atoms, especially 1 nitrogen atom, as heteroatoms in the ring. In the next preferred embodiment of this invention, the A ring is an aromatic 5-membered ring containing a sulfur atom as a heteroatom in the ring or a sulfur atom and a nitrogen atom as heteroatoms in the ring, especially containing a sulfur atom as a heteroatom in the ring.

Preferably, A is selected from the following rings:

Even more preferably, the A ring is selected from the following rings:

The A ring is preferably chosen from the following rings:

Thus, if one of the two most preferred A rings is present in the compounds of formula I, then the compounds of formula I are compounds having formulas la or lb, more specifically, 6,7-dihydro-5H-cyclopenta[b]pyridines of formula Ic (also called pyridines), 5,6,7,8-tetrahydroquinolines of formula Id (which can also be designated as 5,6,7,8-tetrahydro[b]pyridines), 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridines of formula Ie, 5,6-dihydro-4H-cyclopenta[b]thiophenes of formula If, 4,5,6,7-tetrahydrobenzo[b]thiophenes of formula Ig, or 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophenes of formula Ih, respectively. In compounds of formulas la to Ih, the number n in the residues R<2> to R<5> may have any of the preferred or specific meanings indicated above or below. It is preferable that R<1> is selected from the group consisting of: H, C1-C4-alkyl; C1-C4-Alkoxy; CF3; halogen; - CN; Ci-C4-alkyl-S(0)m- and unsubstituted or at least monosubstituted phenyl or heteroaryl, whose substituents are selected from the group consisting of: halogen, -CN, Ci-C3-alkyl, CrC3-alkoxy and CF3, and where the heteroaryl is selected from the group consisting of 5-membered and 6-membered heterocycles, containing one or more heteroatoms, which are selected from the group consisting of N, O and S. More preferably is that R<1> represents H, halogen or C1-C4-alkyl.

It is preferable that R<2> is selected from the group consisting of H, halogen, -CN and C1-C4-alkyl, more preferably from the group consisting of H, halogen and d-C4-alkyl. Even more preferably, R<2>represents H.

Preferably R<3> is selected from the group consisting of H, halogen, -CN and Ci-C4-alkyl, more preferably from the group consisting of H, halogen and Ci-C4-alkyl. Even more preferably, R<3>represents H.

Preferably, R<4> is selected from the group consisting of H, C1-C4-alkyl; d-C4-Alkoxy; CF3; halogen; -CN; Ci-C4-alkyl-S(0)m- and unsubstituted or at least monosubstituted phenyl or heteroaryl, whose substituents are selected from the group consisting of halogen, -CN, d-C3-alkyl, Ci-C3-alkoxy and CF3, and heteroaryl is selected from the group consisting of 5-membered and 6-membered heterocycles, containing one or more heteroatoms, which are selected from the group of N, O and S. It is preferable that R<4> represents H, halogen or C1-C4-alkyl.

It is particularly preferred that each of R<1>, R<2>, R<3> and R<4> represents H. As an example of compounds in which R<1>, R<2>, R<3> and R<4> represent H, there may be mentioned compounds with the formulas I, Ik, Im, In, Io and Ip, in which R<5> has any of the general, or preferred, or specific meanings indicated above or below.

It is preferred that R<5> represents an Ar or Hetar group, both unsubstituted or carrying one or more identical or different substituents selected from the group consisting of: halogen, -CN; NH2; unsubstituted or at least monosubstituted C1-C8-alkyl, C2-C8-alkenyl, d-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkylamino and di(C1-C8-alkyl)amino,

whose substituents are selected from the group consisting of F, OH, C1-C6-Alkoxy, phenoxy, C1-C6-alkylmercapto, NH2, C1C6-alkylamino and di(C1C6-alkyl)amino; C3-C5-alkanediyl; phenyl; heteroaryl; d-Cralkyl substituted with phenyl or substituted with heteroaryl; CF3; OH; phenoxy; benzyloxy; (Ci-Ce-alkylJ-COO; S(0)m-(Ci-C6)-alkyl, which may optionally be substituted with OH or Ci-Ce- alkoxy; S(0)m-phenyl; S(0)m-heteroaryl; SH; phenylamino; benzylamino; (Ci-C6-alkyl)-C0NH-; (Ci-C6-alkyl)-CON(Ci-C4-alkyl)-; phenyl-CONH-; phenyl-CO-; heteroaryl-CON-; -OCH20-;

-CH2CH20-; COO(C1-C6-alkyl); -CONH2; -CONH(C1-C6-alkyl); -CON-di(d-C6-

alkyl)); C(NH)-NH2; SO2NH2; SO2NH(C1C6-alkyl); -SO2NH(phenyl); -SO2N(di(C1C6-alkyl)); C1-C6-alkyl-SO2NH-; (C 1 -C 6 -alkyl)-SO 2 N(C 1 -C 6 -alkyl)-; phenyl-SO 2 NH-; phenyl-SO 2 N(C 1 -C 6 -alkyl)-; heteroaryl-SO 2 NH-; heteroaryl-SO2N(Ci-C6-alkyl)- and the rest of a saturated or monosaturated aliphatic, mononuclear 5-membered to 7-membered heterocycle, containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, heterocycle which can be substituted with one or more substituents selected from the group consisting of halogen, Ci-C3-alkyl, C 1 -C 3 -Alkoxy, OH, oxo and CF 3 , and wherein said heterocycle may optionally be fused to said A group or said Hetar group; wherein all heteroaryl, phenyl, heteroaryl-containing groups and phenyl-containing groups, optionally present in said substituents of said A group or said Hetar group, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, Ci-C3-alkyl, OH,

C1-C3-alkoxy and CF3.

It is preferable that R<5> represents an Ar or Hetar group, both unsubstituted or carrying one or more identical or different substituents selected from the group consisting of: halogen, -CN; NH2; unsubstituted or at least monosubstituted Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, d-C3-alkoxy, CrC4-alkylamino and di(Ci-C4~alkyl)amino, whose substituents are selected from the group consisting of F, Ci-C3-alkoxy, Ci-C3-alkylmercapto, NH2; C3-C5-alkanediyl; phenyl; heteroaryl; C1-C2-alkyl substituted with phenyl or substituted with heteroaryl; CF3; OH; (C 1 -C 4 -alkyl)-COO; S(O)m-(C1-C4)-alkyl, (d-C4-alkyl)-CONH-; (C 1 -C 4 -alkyl)-CON(C 1 -C 4 -alkyl)-; (C 1 -C 4 -alkyl)-CO-; phenyl-CO-; heteroaryl-CO-, CF3-CO-; -OCH20-; -OCF20-; -OCH2CH20-; -CH2CH20-; COO(C 1 -C 6 -alkyl); -CONH2; -CONH(C1C4-alkyl); -CON-di(CrC4-alkyl)); C(NH)-NH2; SO2NH2; SO2NH(C1-C4-alkyl); -SO2NH(phenyl); -SO2N(di(d-C4-alkyl)); CrC4-alkyl-SO2NH-; (C 1 -C 4 -alkyl)-SO 2 N(C 1 -C 4 -alkyl)-; and the residue of a saturated or at least monosaturated aliphatic, mononuclear 5-membered to 7-membered heterocycle, containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, heterocycle, which may be substituted with one or more substituents selected from the group consisting of halogen, Ci-C3-alkyl, Ci-C3- alkoxy, OH, oxo and CF3, and where mentioned the heterocycle may optionally be fused with said A group or said Hetar group; wherein all heteroaryl, phenyl, heteroaryl-containing groups and phenyl-containing groups, optionally present in said substituents of said A group or said Hetar group, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, CrC3-alkyl, OH,

C1-C3-alkoxy and CF3.

Even more preferably, R<5> represents a phenyl or Hetar group, both unsubstituted or bearing one or more identical or different substituents selected from the group consisting of: halogen, -CN; NH2; unsubstituted or at least monosubstituted

Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C3-alkoxy, Ci-C4-alkylamino and di(Ci-C4-alkyl)amino, the substituents of which are selected from the group consisting of F, Ci-C3-alkoxy, C1-C3-alkylmercapto, NH2; C3-C5-alkanediyl; phenyl; heteroaryl; C1-C2-alkyl substituted with phenyl or substituted with heteroaryl; CF3; OH; (C 1 -C 4 -alkyl)-COO; S(O)m-(C1-C4)-alkyl, (C1-C4-alkyl)-CONH-; (C 1 -C 4 -alkyl)-CON(C 1 -C 4 -alkyl)-; (C 1 -C 4 -alkyl)-CO-; phenyl-CO-; heteroaryl-CO-, CF3-CO-; -OCH20-; -OCF20-; -OCH2CH20-; -CH2CH20-; COO(Ci-Ce-alkyl); -CONH2; -CONH(C1-C4-alkyl); -CON-di(C1-C4-alkyl)); C(NH)-NH2; SO2NH2; SO2NH(C1C4-alkyl); -SO2NH(phenyl); -SO2N(di(C1C4-alkyl)); d-C4-alkyl-SO2NH-; (C 1 -C 4 -alkyl)-SO 2 N(C 1 -C 4 -alkyl)-; and the remainder of a saturated or at least monosaturated aliphatic, mononuclear 5-membered to 7-membered heterocycle, containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, the heterocycle, which may be substituted with one or more substituents selected from the group consisting of halogen, Ci-C3-alkyl, CrC3-alkoxy, OH, oxo and CF3, and where said heterocycle may optionally be fused with said phenyl or said Hetar group; wherein all heteroaryl, phenyl, heteroaryl containing groups and phenyl containing groups, optionally present in said substituents of said phenyl or said Hetar groups, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, Ci-C3-alkyl, OH,

C1-C3-alkoxy and CF3.

It is even more preferred that R<5> represents a phenyl or Hetar group, both unsubstituted or carrying one or more identical or different substituents selected from the group consisting of: F; Cl; Br; C1-C3-alkyl, C1-C3-alkoxymethyl, 2-amino-3,3,3-trifluoropropyl-; CF3; C3-C5-alkanediyl; phenyl; heteroaryl; benzyl; heteroaryl-methyl; OH; C1-C3-Alkoxy; phenoxy; trifluoromethoxy; 2,2,2-trifluoroethoxy; (C 1 -C 4 -alkyl)-COO; C1-C3-alkylmercapto; phenylmercapto; C 1 -C 3 -alkylsulfonyl; phenylsulfonyl; NH2; C1-C4-alkylamino; di(C 1 -C 4 -alkyl)amino; (d-Cs-alkylJ-CONH-; (CrC3-alkyl)-SO2NH-; (Ci-C3-alkyl)-CO-; phenyl-CO-; -OCH20-; -OCF20-; -CH2CH20-; COO(Ci-C4-alkyl); -CONH2; -CONH(d-C4-alkyl); -CON-di(Ci-C4-alkyl)); -CN; SO2NH2; SO2NH(C1-C4-alkyl); -SO2N(di(C1C4-alkyl)); pyrrolidinyl; piperidinyl; morpholinyl and thiomorpholinyl; where all heteroaryl, phenyl, heteroaryl-containing groups and phenyl-containing groups, optionally present in said substituents of said phenyl or said Hetar group, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, Ci-C3-alkyl, OH, Ci-C3-alkoxy and CF3.

It is most preferred that R<5> is selected from the group consisting of: 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-(Ci-C3-alkoxy)-phenyl, 4-trifluoromethoxyphenyl, 2-bromo-4-fluorophenyl, 2-chloro-4-fluorophenyl, 3,4-dimethylphenyl, 4-chloro-2-methylphenyl, 2-hydroxymethylphenyl. 2-hydroxy-4-ethoxyphenyl, 2-methoxy-4-methylphenyl, 4-phenoxyphenyl, 3-fluoro-4-methylphenyl, benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, 1 -(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazol-4-yl, 1 -(4-trifluorophenyl)-3,5-dimethyl-1 H -pyrazol-4-yl, 1 H -benzotriazol-5-yl, 1 H -indol-4-yl, 1 H -indol-6-yl, 1 -isopropyl-2-trifluoromethyl-1 H -benzimidazol-5-yl, 1 -methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-6-yl, 1 -phenyl-5-trifluoromethyl-1 H -pyrazol-4-yl, 2-(2-hydroxy-pyridin-4-yl)-1 H -benzimidazol-5-yl, 2-(4-cyanophenyl)-1 H -benzimidazol-5-yl, 2,4-dimethoxyoxazol-5-yl, 2,4-dimethylpyrimidin-5-yl, 2,5-dimethylthiazol-5-yl. H-pyrazol-3-yl, 2,5-dimethyl-1 -phenyl-1H-pyrrol-3-yl, 2,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrrol-3-yl, 2,5-dimethyl-2H-pyrazol-3-yl, 2,6-dichloropyridin-3-yl, 2,6-dimethoxypyridin-3-yl, 2,6-dimethylpyridin-3-yl, 2-amino-4,6-dimethylpyridin-3-yl, 2-amino-6-chloropyridin-3-yl, 2-aminopyridin-3-yl, 2-chloro-6-methylpyridin-3-yl, 2-chloropyridin-4-yl, 2-cyclopropylM-methylthiazol-5-yl, 2-dimethylaminopyridin-3-yl, 2-ethyl-5-methyl-2H-pyrazol-3-yl, 2-hydroxy-6-methylpyridin-3-yl, 2-methyl-1 H-benzimidazol-5-yl, 2-methyl-3H-benzimidazol-5-yl, 2-methylpyridin-3-yl, 2-methyl-6-trifluoromethylpyridin-3-yl, 2-methylthiazol-5-yl, 2-(morpholin-4-yl)-pyrimidin-5-yl, 2-(Pyrrolidin-1-yl)-pyridin-4-yl, 3,5-dimethyl-1 H -pyrazol-4-yl, 3-amino-5,6-dimethylpyrazin-2-yl, 3-amino-5-methylpyrazin-2-yl, 3-aminopyrazin-2-yl, 3-dimethylamino-4-methylphenyl, 3-amino-5,6-dimethylpyrazin-2-yl, 1 H H-benzimidazol-5-yl, 3-methylsulfonyl-amino-2-methylphenyl, 3-methylsulfonylaminophenyl, 3-methylisoxazol-4-yl, 3-(morpholin-4-yl)-phenyl, 3-(piperidin-1-yl)-phenyl, 3-(pyrrolidin-1-yl)-phenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4,6-dimethylpyridin-3-yl, 4-amino-2-ethylsulfanylpyrimidin-5-yl. 4-amino-2-methyl-pyrimidin-5-yl, 4-chloro-3-methylsulfonylaminophenyl, 4-chloro-3-sulfamoylphenyl, 4-methyl-3-methylaminophenyl, 4-methylthiazol-5-yl, pyridin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-amino-1-phenyl-1-pyrazol-4-yl, 5-methylsulfonyl-2-methylphenyl, 5-methyl-1-phenyl-1 H-pyrazol-4-yl, 5-methylisoxazol-3-yl, 5-methylpyridin-3-yl, 5-methylpyridin-2-yl, 6-chloropyridin-3-yl, 6-cyanopyridin-3-yl, 6-dimethylaminopyridin-3-yl, 6-ethynylpyridin-3-yl, 6-methoxymethylpyridin-3-yl, 6-Methoxypyridin-3-yl, 6-methyl-2-methylaminopyridin-3-yl, 6-methylaminopyrazin-2-yl, 6-methylpyridin-3-yl, 6-(morpholin-4-yl)-pyridin-3-yl, 6-(pyrrolidin-1-yl)-pyridin-3-yl, imidazol[1,2-a]pyridin-3-yl, 6-trifluoromethylpyridin-3-yl, pyrimidin-4-yl, 4-methylsulfanylphenyl, 4-ethylsulfanylphenyl, 3-Methoxycarbonylphenyl, 4-Methoxycarbonylphenyl, 3-Ethoxycarbonylphenyl, 4-Ethoxycarbonylphenyl, 2-Bromo-4-chlorophenyl, 2,3-Dichlorophenyl, 3-Chloro-4-(isopropylsutphonyl)thiophen-2-yl, 4-Bromo-2-chlorophenyl, 4-Methoxyphenyl, 3-Methoxyphenyl, 2-methyl-thiophen-3-yl, 3-chloro-4-methyl-thiophen-2-yl, 5-bromo-thiophen-2-yl, 5-chloro-thiophen-2-yl, 5-methyl-thiophen-2-yl, 4-methyl-thiophen-2-yl, 3-methyl-thiophen-2-yl, 5-acetyl-thiophen-2-yl, pyridin-3-yl, pyridin-4-yl, 4-trifluoromethylphenyl, 4-ethylaminophenyl, 4-methylaminophenyl, 2-aminophenyl, 4-bromo-2-fluorophenyl, 3-chlorophenyl, 3- chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 2-chloro-3-methylphenyl, 2-methylphenyl, 2-acetoxy-4-ethoxyphenyl, 2-acetoxy-4-methoxyphenyl, 4-trifluoromethyl-sulfanylphenyl, naphthalen-2-yl, 1,1-dimethylindan-4-yl, 3-isobutyrylaminophenyl, 3-(2,2-dimethylpropionylamino)phenyl, 2-bromophenyl, 2-fluorophenyl, 3-bromo-5-methylthiophen-2-yl, 3-chloro-6-fluorobenzo[b]thiophen-2-yl, and 3,4-dichlorobenzo[b]thiophen-2-yl.

It is preferred that the heteroaryl is a residue of a 5-membered to 10-membered aromatic, monocyclic or bicyclic heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. It is preferred that the heteroaryl is selected from the group consisting of furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridazinyl, pyrazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, indolyl, benzofuranyl, benzodioxolyl, benzothiophenyl and indazolyl.

It is preferred that the Hetar group represents the residue of a 5-membered to 10-membered aromatic, monocyclic or bicyclic heterocycle, containing 1, 2 or 3 heteroatoms, selected from the group consisting of N, 0 and S. More preferably, the heteroaryl is selected from the group consisting of furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridazinyl, pyrazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, indolyl, benzofuranyl, benzodioxolyl, benzothiophenyl and indazolyl.

Preferably, aryl is phenyl.

Preferably m is 0 or 2.

Preferably, n is 1 to 3.

In a preferred embodiment of the present invention, compounds of formula I are acylated, with a fused heteroaryl, cyclopentenylamines of the formula lq (designated also as heteroarene derivatives with a fused cyclopenta residue), or acylated cycloheptenylamines with a fused heteroaryl of the formula lr (designated also as heteroarenes with a fused cyclohepta residue). In compounds of formulas lq and lr, ring A and residues R<1> to R<5> may have any general, or preferred, or specific meaning indicated above or below.

Preferred compounds of formula I are those compounds in which one, or some, or all of the structural residues and groups contained therein have the preferred meanings, more preferred meanings, even more preferred meanings or the most preferred meanings, which are defined above, all combinations of those preferred meanings, etc. and/or specific meanings of the group that is the subject of this invention. With respect to all preferred compounds of formula I, this invention also includes all stereoisomeric forms and mixtures thereof, in all ratios, and pharmaceutically acceptable salts thereof.

As examples of specific compounds, which are the subject of this invention, in all their stereoisomeric forms and in the form of their mixtures in all ratios, and in the form of their pharmaceutically acceptable salts, the following compounds can be mentioned: 2,4-dimethyl-N-(6,7I8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)benzamide, 2,4- dichloro-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)benzamide, 2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid (6,7,8,9- 5H-cyclohepta[b]pyridin-8-yl)amide,

2,6-dimethyl-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)nicotinamide, 6-methoxymethyl-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)nicotinamide, 6-methoxy-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)nicotinamide, 2.5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid (6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)amide,

2-methyl-1H-benzimidazole-5-carboxylic acid (6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)amide,

2,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-8-yl)amide,

2.4-dichloro-N-(6l7-dihydro-5H-[1]pyridin-6-yl)benzamide,

2.5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylic acid (6,7-dihydro-5H-[1]pyridin-6-yl)amide,

2,5-dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrrole-3-carboxylic acid (6,7-dihydro-5H-[1]pyridin-6-yl)amide,

N-(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)-4-fluorobenzamide, 4-chloro-N-(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)benzamide, N-(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)-2,4-dimethylbenzamide, dichloro-N-(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)benzamide, 2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amide, N-(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)-2,6-dimethylnicotinamide N-(5,6-dihydro^H-cyclopenta[b]thiophen-5-yl)-6-methoxymethylnicotinamide, N-(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)-6-methoxynicotinamide, 2.5- dimethyl-1 -phenyl-1 H-pyrrole-3-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amide,

2-methyl-1H-benzimidazol-5-carboxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amide,

2,5-Dimethyl-1-(pyridin-4-ylmethyl)-1H-pyrrole-3-caroxylic acid (5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amide.

The compound of formula I or its salt can be obtained, for example, by a process consisting of the acylation of a cycloalkenylamine with a fused heteroaryl, of formula II, with a carboxylic acid of formula R<5->COOH or its derivative, a process that is also the subject of this invention.

Suitable derivatives of carboxylic acids of the formula R<5->COOH are, for example, carboxylic acid chlorides, esters, including C1-C4-alkyl esters, such as methyl esters or ethyl esters, optionally substituted aryl esters, such as phenyl esters or nitrophenyl esters, or activated esters, or anhydrides, or mixed anhydrides. In the compounds of formula II and carboxylic acids of the formula R<5->COOH and their derivatives, the groups R<1>, R<2>, R<3>, R<4> and R<5> have the meanings indicated above for the compounds of formula I, or in addition, the functional groups may be present in a protected form or in the form of a precursor. For example, when obtaining a compound of formula I containing an acidic carboxyl group or an amino group, it may be convenient that during the acylation reaction these groups are present in a protected form, for example as an ester, such as a tert-butyl ester or a benzyl ester, instead of a free carboxyl group, or as an acylated amino group, such as a tert-butoxycarbonylamino group, or a benzyloxycarbonylamino group, instead of a free amino group, and immediately after acylation the desired end groups are released deprotection. Strategies for selecting a suitable protecting group, which can be used in the synthesis of compounds of formula I, are known to the person skilled in the art. An example of a precursor group of a functional group is a nitro group, which can be converted to an amino group by reduction, for example, catalytic hydrogenation, after an acylation reaction.

Acylation reactions can be carried out under standard conditions known to a person skilled in the art. In many cases it is convenient to carry out the reaction in an inert solvent or diluent, for example in a hydrocarbon or chlorinated hydrocarbon such as toluene, 1,2-dichloroethane or methylene chloride, in an ether such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, in an alcohol such as methanol, ethanol or isopropanol, in an amide such as N,N-dimethylformamide, or in N-methylpyrrolidone, acetonitrile, water, or in a mixture of two or more solvents or diluents. Depending on the individual case, it may be convenient to carry out the reaction in the presence of a base, for example an inorganic base, such as sodium hydroxide, sodium carbonate or sodium bicarbonate, or an organic base, such as triethylamine, ethyldiisopropylamine, N-ethylmorpholine or pyridine, and/or in the presence of an acylation catalyst, such as 4-dimethylaminopyridine.

If a carboxylic acid of the formula R<5->C00H is used in the acylation reaction of a compound of formula II, it is often convenient to activate the acid or its salt with a condensing agent or coupling agent, for example, with an agent such as those commonly used in peptide cleavage, when forming an amide bond. Examples of suitable coupling agents are carbodiimides, such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, TOTU, ie. 0-((cyano(ethoxy-carbonyl)methylene)amino)-N,N,N',N'-tetramethyluronium tetrafluoroborate, HATU, i.e. 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, chloroformic acid esters such as ethyl chloroformate or isobutylchloroformate, tosyl chloride, propylphosphonic anhydride or carbonyldiimidazole. Depending on the case, the suitable reaction temperature may be within a wide range. For example, when a carboxylic acid is used in the acylation reaction in the presence of a coupling agent or carboxylic acid chloride, the reaction can often be conducted at room temperature.

After the acylation reaction, in addition to the above-mentioned deprotection of the protected groups, or the conversion of the precursor group to the desired final group, optional additional functionalizations or modifications of the obtained compounds can be carried out, so suitable functional groups can be, for example, esterified, amidated, transesterified, alkylated, suffonated, acylated, reduced, oxidized, converted into a salt, or subjected to other reactions.

The starting compounds for the preparation of compounds of formula I are commercially available or can be obtained according to procedures analogous to those in the literature. Routes for obtaining compounds of formula II are, for example, conversion of ketones of formula

III to the oxime of formula IV, then the conversion of the latter into the compound of formula II, and the conversion of the carboxylic acid of formula V into the azide of the carboxylic acid of formula VI, then the conversion of the latter into the compound of formula II. Said conversions can be performed under standard conditions known to a person skilled in the art. For example, a ketone of formula III can be converted to an oxime of formula IV by treatment with an organic nitrite, such as isoamyl nitrite, in the presence of hydrochloric acid, then reduction of the oxime group, giving an amino group, and reduction of the C=0 group in the benzyl position, giving a CH2 group, can be done simultaneously, by catalytic hydrogenation in the presence of, for example, palladium. A carboxylic acid of formula V can be converted to an azide of a carboxylic acid of formula VI by reaction, for example, with diphenylphosphoryl azide, the latter undergoing a Curtius displacement.

The starting compounds of formula III and V can be prepared as described, e.g. in JP 2-255664; EP 853083; US 6,258,829; US 6,278,027; CA 2151443; GB 2280438; Schenone et al., J. Heterocycl. Chem., 1982, 19, 1355; Bianchi et al., J. Chem. Res., Synop., 1981, 6; Muraro et al., Bulli. Soc. Chm. Fr., Pt. 2, 1973, 335; Muraro et al., C. R. Acad. Sci., Ser. C, 1973, 273, 1362; MacDowell et al., J. Org. Chem., 1967, 32, 1226; Ravina et al., J. Med. Chem., 1999, 42, 2774; Nayyar et al., J. Org. Chem., 1997, 62, 982; Binder et al., Monatsh. Chem., 1998, 129, 887; Eesterwelle et al., 1995, 124, 571; Huang et al., Synth. Commun., 1998, 28, 2736; Reimann et al., Pharmazie, 1995, 50, 589; Caprathe et al., J. Med. Chem. 1991, 34, 2736; Hoffman et al., J. Org. Chem. 1984, 49, 193; Schroeder et al., Eur. J. Med. Chem. - Chim. Ther., 1979, 14. 309; Ruangsivanand etal.,Chem. Ber., 1970, 103, 2403; Dammertz et al., Are. Pharm., 1977, 310, 172; Hicks et al., J. Chem. Soc, Perkin Trans., 1984, 1, 2297; Jones et al., J. Chem. Soc, Perkin Trans., 1973, I, 968; US 5,753,662 or VVO 94/04531, or using methods analogous to those described in the cited literature.

All reactions for the synthesis of compounds of formula I are well known to the skilled person, and can be carried out under standard conditions, according to procedures analogous to those described in the literature, for example in Houben-Weyl "Methoden der Organischen Chemie", Thieme-Verlag, Stuttgart, or in "Organic Reactions<B>, John Wiley and Sons, New York. As mentioned above, depending on the circumstances of the individual case, in order to avoid side reactions during the synthesis of compounds of formula I, it may be necessary or convenient to temporarily block functional groups by introducing protective groups in the last stage of synthesis, or to introduce functional groups in the form of precursor groups, which are converted into desired functional groups at a later stage. Such strategies for the synthesis of both protective groups and precursor groups, which are suitable in certain cases, are known to those skilled in the art. If desired, compounds of formula I can be purified by conventional procedures purification, for example, by recrystallization or chromatography.

The compounds of formula I are useful pharmaceutically active compounds that upregulate the secretion of endothelial NO synthase and can be used as medicaments for the treatment of various diseases. In the context of the present invention, treatment is understood to include therapy, including alleviation and progression of disease symptoms, and prevention or prophylaxis of disease symptoms, such as, for example, prevention of the onset of asthmatic disease symptoms, or prevention of myocardial infarction or recurrent myocardial infarction, in appropriate patients. Diseases or disease symptoms can be acute or chronic. Diseases that can be treated with compounds of formula I are, for example, cardiovascular diseases, such as stable and unstable angina pectoris, coronary heart disease, Prinzmetal's angina (spasm), acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral arterial occlusive disease (PAOD), endothelial dysfunction, atherosclerosis, restenosis, endothelial damage after PTCA, hypertension, including essential hypertension, pulmonary hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), erectile dysfunction and ventricular arrhythmias. In addition, compounds of formula I lower cardiovascular risk in postmenopausal women and in women taking contraceptives. Compounds of formula I can still be used in treatment, i.e. therapy and prevention of diabetes and complications from diabetes (nephropathy, retinopathy), angiogenesis, bronchial asthma, chronic kidney disorders, liver cirrhosis, osteoporosis, manifestation of limited memory or limited learning ability. Preferred indications are stable angina pectoris, coronary heart disease, hypertension, endothelial dysfunction, atherosclerosis and complications from diabetes.

The compounds of formula I can be used in combination with other pharmaceutically active compounds, preferably with compounds capable of enhancing the effect of the compounds of formula I. Examples of such other compounds are statins; ACE inhibitors; AT1 antagonists; argininase inhibitors; PDE V inhibitors; calcium antagonists; alpha blockers; beta blockers; thiamazole (methimazole) and analogous compounds; arginine; tetrahydrobiopterin; vitamins, especially vitamin C and vitamin B6; niacin.

Compounds of formula I and their pharmaceutically acceptable salts, optionally in combination with other pharmaceutically active compounds, can be prescribed to animal beings, preferably mammals, and especially to human beings, as pharmaceutical products, or in a mixture with each other, or in the form of pharmaceutical preparations. Therefore, further objects of the present invention are the compounds of formula I, as defined above, and/or their pharmaceutically acceptable salts, which are used as pharmaceutical products. A further subject of this invention is the use of the compound of formula I and/or its pharmaceutically acceptable salt as an agent for stimulating the transcription of an agent for the upregulation of endothelial NO synthase, for example in conditions in which the increased secretion of said enzyme or an elevated content of NO, or the normalization of a reduced content of NO are desirable in patients, and especially their use in treatment, i.e. therapy and prevention of the above-mentioned syndromes, as well as their use for obtaining medicines for these purposes, where the latter object of this invention expressly also includes the use of compounds of formula I and/or their pharmaceutically acceptable salts, which are conditionally excluded from the above-defined compounds, which are the subject of this invention, as such.

In addition, the subject of this invention are pharmaceutical preparations (or pharmaceutical compositions), which contain an effective dose of at least one compound of formula I and/or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances or liquid carriers and/or additives or supplements.

The pharmaceutical products according to the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, in the form of suppositories. Administration can also be done parenterally, for example, subcutaneously, intramuscularly or intravenously, in the form of a solution for injections or by infusion. Other suitable forms of administration are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays and transdermal therapeutic systems, or administration by inhalation, in the form of nasal sprays or aerosol mixtures, or for example, microcapsules, implants or sticks. The preferred form of prescription depends, among other things, on the disease being treated and its severity.

The amount of the compound of formula I and/or its pharmaceutically acceptable salts in pharmaceutical preparations ranges from about 0.2 to about 800 mg, preferably from about 0.5 to about 500 mg, and especially from about 1 to about 200 mg, per dose, but depending on the type of pharmaceutical preparation it can be higher. Pharmaceutical preparations usually contain from about 0.5 to about 90% by weight of compounds of formula I and/or pharmaceutically acceptable salts thereof. Obtaining pharmaceutical preparations can be done in a known way. In this regard, one or more compounds of formula I and/or their pharmaceutically acceptable salts, together with one or more solid or liquid pharmaceutically acceptable carrier substances and/or additives (or auxiliary substances), if desired, in combination with other pharmaceutically active compounds that have a therapeutic or prophylactic effect, are brought into a suitable form for prescribing or dosage form, from which they can then be used as a pharmaceutical product in human or veterinary medicine.

To obtain pills, tablets, sugar-coated tablets and hard gelatin capsules, for example, lactose, starch, for example corn starch, or starch derivatives, talc, stearic acid and its salts, etc. can be used. Soft gelatin capsules and suppositories may contain, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example solutions for injection, or emulsions and syrups, are for example water, physiological sodium chloride solution, alcohols, such as ethanol, glycerin, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of formula I and their pharmaceutically acceptable salts, and use the obtained lyophilizates, for example, to obtain preparations for injections or infusions. Suitable carriers for microcapsules, implants and rods are, for example, copolymers of glycolic acid and lactic acid.

In addition to one or more compounds of the present invention and carrier substances, the pharmaceutical preparations may also contain additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, coloring agents, flavors, aromatizers, thickeners, diluents, buffering substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing osmotic pressure, coating agents and antioxidants.

The dosage of the compound of formula I and/or a pharmaceutically acceptable salt thereof to be prescribed depends on the individual case and, as usual, is adjusted to the individual circumstances in order to achieve an optimal effect. Thus, it depends on the nature and severity of the disorder to be treated, and also on the sex, age, mass and individual response of the human or animal being to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is used for acute or chronic disease or for prophylaxis, or whether the active compounds are administered with additional compounds of formula I. Typically, the daily dose is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 10 mg/kg, and especially from about 0.3 to 5 mg/kg (in each case mg per kg of body weight) is suitable for administration to an adult, weighing approximately 75 kg, in order to obtain the desired result. The daily dose can be prescribed in one dose only, or, especially if larger doses are prescribed, divided into several, for example, two, three or four individual doses. In some cases, depending on the individual response, it may be necessary to deviate up or down from the given daily dose.

The compounds of formula I may also be used for purposes other than those indicated above. Non-limiting examples are, for diagnostic purposes, such as use for testing cell or tissue samples, use as a biochemical tool, and use as an intermediate to obtain other compounds, e.g. pharmaceutical active compounds.

Examples

HPLC mouthpieces

HPLC procedure a

Column: Daicel Chiralpak AD, 250x4.6 mm, 10 um; eluent: acetonitrile/isopropanol (120/5) + 0.1% diethylamine; flow rate: 1.0 mL/min.

HPLC method b

Column: Merck Purospher, 55x2 mm, 5 pm; eluent A: water + 0.05% trifluoroacetic acid; eluent B: acetonitrile; gradient: from 95% eluent A and 5% eluent B to 5% eluent A and 95% eluent B in 4 min, 5% eluent A and 95% eluent B in 1.5 min; flow rate: 0.5 mL/min.

HPLC procedure c

Column: YMC J'Sphere ODS H80, 33x2 mm, 3 pm; eluent A: water + 0.05% trifluoroacetic acid, eluent B: acetonitrile; gradient: from 90% eluent A and 10% eluent B to 5% eluent A and 95% eluent B in 2.5 min, and 5% eluent A and 95% eluent B in 0.8 min; flow rate: 1.0 mL/min.

HPLC procedure d

Column: Daicel Chiralpak AD, 250x4.6 mm, 10 pm; eluent: n-heptane/isopropanol (10/1); flow rate: 1.0 mL/min.

HPLC procedure

Column: Merck Purospher, 55x2 mm, 5 pm; eluent A: water + 0.1% formic acid; eluent B: acetonitrile + 0.08% formic acid; gradient: from 95% eluent A and 5% eluent B to 5% eluent A and 95% eluent B in 5 min, 5% eluent A and 95% eluent B in 2 min; flow rate: 0.45 mL/min.

Retention times (RT) for HPLC are given in minutes.

General procedures for the acylation of cycloalkenylamines with a fused heteroaryl

General acylation procedure A:

Mix 2.5 mmol of the appropriate amine with 550 mg of triethylamine and 5 mL of dioxane or tetrahydrofuran, then add 2.5 mmol of the appropriate carboxylic acid chloride. The mixture is stirred for 2 hours at room temperature, and then poured into a saturated solution of sodium bicarbonate. The mixture is extracted with ethyl acetate, and the organic solution is dried and concentrated. The residue is purified by preparative HPLC (RP18; acetonitrile/water + trifluoroacetic acid) or flash chromatography on silica gel (methylene chloride or methylene chloride/methanol).

General acylation procedure B:

144 mg (0.44 mmol) of 0-((cyano(ethoxycarbonyl)-methyl)amino)-N,N,N',N'-tetramethyuronium tetrafluoroborate (TOTU) in 1 mL of dimethylformamide and 114 mg (0.88 mmol) of ethyldiisopropylamine are added to 0.4 mmol of the appropriate carboxylic acid, dissolved in 5 mL of tetrahydrofuran. After stirring for 30 min at room temperature, 0.37 mmol of the corresponding amine was added, and the reaction mixture was stirred for 12 h. The reaction mixture is poured into saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase is dried and concentrated. The residue is purified by HPLC (RP18, acetonitrile/water + trifluoroacetic acid) or flash chromatography on silica gel (methylene chloride or methylene chloride/methanol).

General acylation procedure C:

Dissolve 0.4 mmol of the appropriate amine and 75 µL (0.44 mmol) of ethyldiisopropylamine in 2 mL of dimethylformamide, and cool the solution to 0°C. After that, a solution of 54 mg (0.44 mmol) of 4-dimethylaminopyridine in 0.5 mL of dimethylformamide, 0.44 mmol of the corresponding carboxylic acid and a solution of 59 mg (0.44 mmol) of 1-hydroxybenzotriazole in 0.5 mL of dimethylformamide were added, and this mixture was stirred for 20 min at 0°C. Then a solution of 68 mg (0.44 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide in 0.5 mL of dimethylformamide was added, and the mixture was stirred for 12 h at room temperature. The reaction mixture is filtered, and the filter cake is washed twice with 10 mL of ethyl acetate. The solution is washed with 20 mL of 5% sodium chloride solution, the organic phase is separated, dried over Chromabond XTR and evaporated to dryness. If desired, the product is purified by preparative HPLC (RP 18, acetonitrile/water + 0.01% trifluoroacetic acid).

Example 1

N-(6,7-dihydro-5H-[1]pyridin-6-yl)-2.4-dimethylbenzamide (enantiomer 1)

a) 7 - benzylidene - 6 . 7 - dihydro - 5H -[ 1lDyridine

It is heated for 24 h under reflux, 15 g (0.125 mol) of 6,7-dihydro-5H-{1]pyridine, 20.1

g (0.19 mol) of freshly distilled benzaldehyde and 24.5 g (0.24 mol) of acetic anhydride. The reaction mixture is evaporated, the residue is dissolved in methylene chloride, and the solution is extracted with a 1M NaOH solution, and the organic phase is separated and dried. The residue was distilled under reduced pressure to give 19.3 g (75%) of the title compound.

Boiling temperature (0.013 mbar): 150°C. Melting point: 72°C.

b) 5. 6 - dihydro - [ 1lDiridin - 7 - one

Dissolve 19.3 g (0.09 mol) of the compound from step a) in 250 mL of dry methanol, cool to -35°C, then ozonize for 3 hours. 10.56 g (0.17 mol) of dimethylsulfide was added and the reaction was allowed to warm to room temperature overnight. Evaporation and subsequent distillation of the residue under reduced pressure gave 6.6 g of the title compound.

Boiling temperature (0.003 mbar): 150°C.

c) 5H-fluoroiridine-6. 7 - dione 6 oxime

Dissolve 6.6 g (49.6 mmol) of the compound from step b) and 6.97 g (59.5 mmol) of isoamyl nitrite in 150 mL of methanol heated to 45°C, then treat it dropwise with 8 mL of concentrated hydrochloric acid. After stirring for 3 h at 45°C, the mixture was cooled to 0°C, and the precipitated product was collected by vacuum filtration. Yield: 7.3 g (91%).

TLC: Rf = 0.2 (silica gel, methylene chloride/methanol (95/5)).

d) N-(6.7-clihydro-5H-rylDiridin-6-yl)acetamide

Dissolve 18 g (0.11 mol) of the compound from step c) in 500 mL of acetic acid and 500 mL of acetic anhydride, then hydrogenate for 20 h at a pressure of 2 bar in the presence of 5 g of palladium on barium sulfate. The reaction mixture was filtered and evaporated. The residue is dissolved in 1000 mL of ethanol, treated with 10.8 mL of perchloric acid, then hydrogenated for 10 h at 50°C, under a pressure of 3.5 bar, in the presence of 5 g of palladium on activated carbon (10%). The obtained mixture is evaporated, the residue is dissolved in a dilute NaOH solution and extracted with ethyl acetate. Evaporation of the combined organic phases and subsequent chromatography of the residue gave racemic N-(6,7-dihydro-5H-[1]pyridin-6-yl)acetamide.

TLC: Rf = 0.28 (silica gel, methylene chloride/methanol (9/1)).

This racemic acetamide was separated into enantiomers by chiral phase chromatography (Chiralpak AD; eluent: acetonitrile/isopropanol (120/5) + 0.1% diethylamine). The yield of enantiomer 1, N-(6,7-dihydro-5H-[1]pyridin-6-yl)acetamide, was 1.89 g, and the yield of enantiomer 2, N-(6,7-dihydro-5H-{1]pyridin-6-yl)acetamide, was 1.53 g.

Enantiomer 1:

HPLC: RT = 6.40 min (procedure a)

Enantiomer 2:

HPLC: RT = 8.16 min (procedure a)

e) 6H-dihydro-5H-phenylpyridin-6-ylamine (enantiomer 1 and enantiomer 2)

The separated enantiomers of N-(6,7-dihydro-5H-[1]pyridin-6-yl)acetamide are hydrolyzed by heating for 4 h at 150°C, with 20 mL of 6M HCl in a hermetic vessel. Evaporation, then treatment with an excess of 1M NaOH solution, extraction with ethyl acetate, then drying and evaporation of the extracts gave the two enantiomers of N-(6,7-dihydro-5H-[1]pyridin-6-ylamine, in yields of 0.7 g and 0.8 g, respectively).

Enantiomer 1:

MS: m/e = 135 (M+H)<+>. HPLC: RT = 0.13 (procedure c)

Enantiomer 2:

MS: m/e = 135 (M+H)<+>. HPLC: RT = 0.13 (procedure c)

D N -( 6H<tihydro-5H-niDiridin-6-yl)-2A-dimethylbenzamide (enantiomer 1)

The title compound is obtained from the chiral dihydro-5H-[1]pyridin-6-ylamine of step e), according to the general acylation procedure A.

MS: m/e = 267 (M+H)<+>. HPLC: RT = 1.12 min (procedure c).

Example 2

N-(6.7-dihydro-5H-flpyridin-6-yl)-2.4-dimethylbenzamide (enantiomer2)

H3C

The title compound is obtained from the chiral 6,7-dihydro-5H-[1]pyridin-6-ylamine of Example 1, step e), according to the general acylation procedure A.

MS: m/e = 267 (M+H)<+>. HPLC: RT = 1.12 min (procedure c).

Example 3

N-(6.7-dihydro-5H-flpyridine-6-ylM-fluorobenzamide (enantiomer 1)

The title compound is obtained according to the general acylation procedure A, starting from racemic 6,7-dihydro-5H-[1]pyridin-6-ylamine, which is obtained from racemic N-(6,7<lihydro-5H-[1]pyridin-6-yl)acetamide from Example 1, step d), by hydrolysis, analogously to the procedure described in Example 1, step e), then separating the racemic N-(6,7-dihydro-5H-[1 ]pyridin-6-yl)-4-fluorobenzamide by preparative chromatography on a chiral phase (Chiralpak AD; eluent: heptane/isopropanol (10/1)).

MS: m/e = 257 (M+H)<+>. HPLC: RT = 15.66 min (procedure d).

Example 4

N-(6.7- dihydro- 5H-H lpyridin-6-yl)-4-fluorobenzamide (enantiomer 2)

The title compound was obtained as described in Example 3 by resolution of N-(6,7-dihydro-5H-[1]pyridin-6-yl)-4-fluorobenzamide.

MS: m/e = 257(M+H)<+>. HPLC: RT = 14.96 (procedure d).

Example 5

N-(6.7-dihydro-5H-pyridin-6-yl)-2.6-dimethylnicotinamide (enantiomer 1)

The title compound is obtained from the chiral 6,7-dihydro-5H-{1]pyridin-6-ylamine of Example 1, step e), according to the general acylation procedure A.

MS: m/e = 268 (M+H)<+>. HPLC: RT = 0.15 min (procedure c).

Example 6

N-(6.7-dihydro-5H-f1lpyridine-6-yl-6-methoxynicotinamide (enantiomer 1)

The title compound is obtained from the chiral 6,7-dihydro-5H-[1]pyridin-6-ylamine of Example 1, step e), according to the general acylation procedure A.

MS: m/e = 270 (M+H)<+>. HPLC: RT = 0.43 min (procedure c).

Example 7

2- methyl- 3H- benzimidazole- 5 carboxylic acid

(6,7-Dihydro-5H-Mlpyridin-6-yl)amide, (enantiomer 1)

The title compound is obtained from the chiral 6,7-dihydro-5H-[1]pyridin-6-ylamine of Example 1, step e), according to the general acylation procedure A.

MS: m/e = 293 (M+H)<+>. HPLC: RT = 0.17 min (procedure c).

Example 8

N-(6,7-dihydro-5H-f1]pyridin-6-yl)-6-methoxymethylnicotinamide (enantiomer 1)

The title compound is obtained from the chiral 6,7-dihydro-5H-{1]pyridin-6-ylamine of Example 1, step e), according to general acylation procedure B.

MS: m/e = 284 (M+H)<+>. HPLC: RT = 1.77 min (procedure b).

Example 9

2. 2-difluorobenzo[1,3]dioxol-5-carboxylic acid

(6.7-Dihydro-5H-[1lpyridine-6-iDamide (enantiomer 1)

The title compound is obtained from the chiral 6,7-dihydro-5H-[1]pyridin-6-ylamine of Example 1, step e), according to general acylation procedure B.

MS: m/e = 319 (M+H)<+>. HPLC: RT = 1.60 min (procedure c).

Example 10

4-chloro-N-(6.7-dihydro-5H-pyridin-6-yl)benzamide (enantiomer 1),

trifluoroacetic acid salt

The title compound is obtained from the chiral 6,7-dihydro-5H-[1]pyridin-6-ylamine of Example 1, step e), according to the general acylation procedure A.

MS: m/e = 273 (M+H)<+>. TLC: Rf = 0.29 (silica gel, methylene chloride (methanol (95/5)).

Example 11

2, 4- dimethyl-N-(6.7.8.9-tetrahydro-5H-cycloheptaphylpyridin-8-yl)-benzamide

a) 9 - benzylidene - 6 . 7. 8. 9-Tetrahydro-5H-CycloheptafblDyridine

The title compound is obtained from 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine,

analogous to the procedure described in Example 1, step a). The crude material was purified by chromatography on silica gel, using methylene chloride as eluent.

MS: m/e = 236 (M+H)<+>. TLC: Rf = 0.47 (silica gel, n-heptane/ethyl acetate (3/2)).

b) 5. 6. 7. 8 - tetrahydrocycloheDtafblDindin - 9 - one

The title compound is obtained from the compound from step a), analogously to the procedure described in Example 1, step b). The crude material is purified by chromatography on silica gel, using methylene chloride/methanol (98/2) as eluent.

MS: m/e = 162 (M+H)<+>. TLC: Rf = 0.72 (silica gel, methylene chloride/methanol (98/2)).

c) 6. 7-dihydno-5H-cycloheptafb]pindin-8. 9 - dione 8 - oxime

Dissolve 6.7 g (41.6 mmol) of the compound from step b) in 300 mL of diethyl ether, then treat with 10 mL of a saturated solution of hydrogen chloride in diethyl ether. 5.38 g (45.8 mmol) of isoamylnitrite in 500 mL of tetrahydrofuran and 10 mL of a saturated solution of hydrogen chloride in diethyl ether were added to the resulting thick suspension. This mixture was refluxed for 3 h, cooled in an ice bath, and the precipitated product was separated by vacuum filtration. Yield 7.9 g (100%).

MS: m/e = 191 (M+H)<+>. Rf = 0.20 (silica gel, methylene chloride/methanol (98/2)).

d) 6. 7. 8. 9 - tetmhidm - 5H<ikloheDtafblDihdin - 8Chlamin

The title compound is obtained from the compound from step c), analogously to the procedure described in Example 1, steps d) and e). The crude material was purified by chromatography on silica gel, using methylene chloride/methanol (98/2) as eluent.

MS: m/e = 163 (M+H)\ Rf = 0.09 (silica gel, methylene chloride/methanol (98/2)).

e) 2. 4 - dimethyl - N - ( 6 . 7 . 8 . 9 - tetrahydro - 5H - dcloheDtafblDindin - 8 - yl ) benzamide

The title compound is obtained from the compound of step d), according to the general

by the acylation process A.

MS: m/e = 295 (M+H)<+>. HPLC: RT = 3.68 min (procedure b).

Example 12

3- amino- 5- methylpyrazine- 2- carboxylic acid

(5.6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amide

a) 5. 6<lihydro - 4H<cycloDentarbthio1ene - 5Chlamin hydrochloride

Dissolve 2.289 g (13.61 mmol) of 5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylic acid (US A-5753662) in 25 mL of acetonitrile, then add 4.120 g (14.97 mmol) of diphenylphosphorylazide and 1.515 g (14.97 mmol) of triethylamine, and the mixture is stirred for 2.5 h. at room temperature. Then, 11.51 mL (168.4 mmol) of allyl alcohol was added, and the reaction mixture was heated to 50°C overnight. The solvent is evaporated, and the residue is dissolved in ethyl acetate and extracted with a 10% sodium bicarbonate solution. The organic phase is separated, dried and evaporated to dryness. The residue was dissolved in 200 mL of methylene chloride, and 2.60 mL (16.32 mmol) of triethylsilane, 320 µL (2.312 mmol) of triethylamine and 153 mg of palladium acetate were added to the mixture. After stirring for 3 hours at room temperature, the solvent is evaporated, and the residue is dissolved in ethyl acetate, then extracted with a 10% sodium bicarbonate solution. The organic phase is separated and extracted with dilute hydrochloric acid. The combined hydrochloric acid phases were freeze-dried to give 1.44 g of the title compound, which was used in the acylation step without further purification.

b) 3-amino-5-methylpyrazine-2-carboxylic acid

( 5 . 6 - dihydrin>4H - cycloODentarb1thiophene - 5 iDamide

The title compound is obtained from 5,6-dihydro-4H-cyclopenta[b]thiophen-5-ylamine hydrochloride from step a), according to the general acylation procedure C.

MS: m/e = 275 (M+H)<+>. HPLC: RT = 3.62 min (procedure e).

Examples 13-31, which follow, are prepared from the 5,6-dihydro-4H-cyclopenta[b]thiophen-5-ylamine hydrochloride of Example 12, step a), according to the general acylation procedure of C.

Example 13

N-(5,6-dihydro-4H-cyclopentaphenylthiophen-5-yl)-2,6-dimethylnicotinamide,

trifluoroacetic acid salt

MS: m/e = 273 (M+H)<+>. HPLC: RT = 1.80 min (procedure e).

Example 14

N-(5,6-Dihydro-4H-Cyclopentafbltiofen-5-yl)-6-Methoxynicotinamide

MS: m/e = 275 (M+H)<+>. HPLC: RT = 3.30 min (procedure e).

Example 15

2- methyl- 3H- benzimidazole- 5- carboxylic acid

( 5. 6- dihydro- 4H- cyclopentarbltiophene- 5- iOamid. salt of trifluoroacetic acid

MS: m/e = 298 (M+H)<+>. HPLC: RT = 1.93 min (procedure e).

Example 16

5-methyl-1-phenyl-1H-pyrazoM-carboxylic acid

(5.6-dihydro-4H-cyclopentarbltiofen-5-yl)amide

MS: m/e = 324 (M+H)<+>. HPLC: RT = 3.67 min (procedure e).

Example 17

1- phenyl- 5- trifluoromethyl- 1 H- pyrazole- 4- carboxylic acid

(5. 6-dihydro-4H-cyclopentarbThiophen-5-inamide

MS: m/e = 378 (M+H)<+>. HPLC: RT = 4.02 min (procedure e).

Example 18

2. 5-dimethyl-1-pyridin-4-ylmethyl-1H-pyrrole-3-carboxylic acid

(5, 6- dihydro- 4H- cyclopentabltiofen- 5- yl) amide, fluoroacetic acid salt

MS: m/e = 352 (M+H)<+>. HPLC: RT = 2.37 min (procedure e).

Example 19

2. 4-dimethylthiazole-5-carboxylic acid

(5,6-dihydro-4H-cyclopentarb]thiophen-5-yl)amide

MS: m/e = 279 (M+H)<+>. HPLC: RT = 3.12 min (procedure e).

Example 20

1, 3- dimethyl- 1 H-pyrazoM- carboxylic acid

(5,6-dihydro-4H-cyclopentaphenylthiophen-5-yl)amide

MS: m/e = 262 (M+H)<+>. HPLC: RT = 2.79 min (procedure e).

Example 21

2-amino-N-(5.6-dihydro-4H-cyclopentarb1thiophene-5-innicotinamide.

trifluoroacetic acid salt

MS: m/e = 260 (M+H)<+>. HPLC: RT = 1.85 min (procedure e).

Example 22

N-(5.6-dihydro-4H-cyclopentarbthiophene-5-yn-6-methylnicotinamide,

trifluoroacetic acid salt

MS: m/e = 259 (M+H)<+>. HPLC: RT = 2.17 min (procedure e).

Example 23

2- chloro-N-(5.6-dihydro-4H-cyclopentaphenylthiophen-5-yl)-6- methylnicotinamide

MS: m/e = 293 (M+H)<+>. HPLC: RT = 3.20 min (procedure e).

Example 24

N-(5.6-dihydro-4H-cyclopentarb1thiophen-5-yl)-6-methoxymethylnicotinamide.

trifluoroacetic acid salt

MS: m/e = 289 (M+H)<+>. HPLC: RT = 2.84 min (procedure e).

Example 25

3- aminopyrazine- 2- carboxylic acid

(5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)amide

MS: m/e = 261 (M+H)<+>. HPLC: RT = 3.42 min (procedure e).

Example 26

2. 3- dichloro-N-(5. 6- dihydro- 4H- cyclopentarbTthiophen- 5- yl) benzamide

MS: m/e = 312 (M+H)<+>. HPLC: RT = 3.90 min (procedure e).

Example 27

N-(5.6-dihydro-4H-cyclopentarb1thiophene-5-yn-2,4-dimethylbenzamide

MS: m/e = 272 (M+H)<+>. HPLC: RT = 3.87 min (procedure e).

Example 28

N-(5.6-dihydro-4H-cyclopentarb1thiophene-5-yn2.4-difluorobenzamide

MS: m/e = 280 (M+H)<+>. HPLC: RT = 3.79 min (procedure e).

Example 29

N-(5.6-Dihydro-4H-Cyclopentarblthiophen-5-yl)-3-Methylsulfonylaminobenzamide

MS: m/e = 337 (M+Hf. HPLC: RT = 3.12 min (method e).

Example 30

N-(5.6-dihydro-4H-cyclopentarb1thiophene-5-yn-6-(morpholine, 4-ichnicotinamide).

trifluoroacetic acid salt

MS: m/e = 330 (M+H)<+>. HPLC: RT = 2.73 min (procedure e).

Example 31

N-(5.6-dihydro-4H-cyclopentarb1thiophene-5-yn-3-(morpholine-4-inbenzamide)

MS: m/e = 329 (M+H)<+>. HPLC: RT = 3.43 min (procedure e).

Determination of eNOS transcriptional activation

Activation of eNOS transcription was determined as detailed in Li et al., "Activation of protein kinase C alpha and/or epsilon enhances transcription of the human endothelial nitric oxide synthase gene", Mol. Pharmacol., 1998, 53, 630.

Briefly, a 3.5 kB 5' fragment from the start codon of the eNOS gene is cloned, sequenced and cloned into firefly secreted luciferase plasmids to monitor eNOS promoter activation via reporter gene activity. A human endothelial cell strain stably transfects and secretes this reporter-promoter construct, which is used to test compounds. Cells were incubated for 18 h with the compounds.

All compounds were dissolved in sterile dimethylsulfoxide (DMSO). A final concentration of 0.5% DMSO in the complete medium was allowed. Induction of reporter gene expression in these cells is measured using a standard luciferase assay system (Promega, catalog number E150) according to the manufacturer's instructions. Luciferase induction in cells incubated with compounds is compared to those incubated with solvent alone. The ratio of these activities (transcription induction ratio, TIR) is plotted as a function of compound concentration. Typically, TIR values start at low concentrations with a ratio of 1, indicating no effect of the compound, and extend to a maximum TIR value, TIR(max), indicating an increase in eNOS transcription. EC50 values for compound concentration-dependent transcription induction ratios are determined graphically.

The effect of the compound on eNOS transcription was confirmed in a second test, based on the detection of eNOS protein. Primary human umbilical vein endothelial cells (HUVEC) are isolated and cultured according to standard procedures. The fused cells are incubated with the compounds for 18 h, and the effect of eNOS protein secretion is determined by the procedure of quantitative VVestem blotting. After compound incubation, HUVECs were lysed in ice-cold lysis buffer containing 10 mM Tris-HCl, pH 8.0, 1% SDS, and protease inhibitors. The lysate is subjected to standard denaturation by polyacrylamide gel electrophoresis and stained on nitrocellulose membranes. Using a specific primary monoclonal antibody (Transduction Laboratories, UK) and a labeled alkaline phosphatase secondary antibody (Jackson Labs.), a specific band of eNOS protein is observed, and quantified based on the chemifluorescence detection method. The results are shown in the Table below.

The effect of the compounds of this invention can be tested also in the following animal models (experiments on animals were performed in accordance with the German law on animal protection and in accordance with the instructions for the use of experimental animals, given in "The Guide for the Care and Use of Laboratory Animals of the US National Institutes of Health").

Animals and treatment (Experiments A-C)

Mice deficient in ApoE and eNOS (C57BL/6J background, Jackson Laboratories, Bar Harbor, ME) were used. All animals are 10 to 12 weeks old and weigh 22 to 28 g. Three days before surgery, mice were divided into 4 groups (apoE control, n = 10 to 12; apoE with test compounds, n = 10 to 12; eNOS control, n = 10 to 12; eNOS with test compounds, n = 10-12) and received either standard rodent chow (containing 4% fat and 0.001% cholesterol; referred to as placebo below). group) or standard rodent chow + test compound (10 or 30 mg/kg p.o.).

A. Antihypertensive effect in AooE knockout mice

Blood pressure was determined in conscious mice using a computerized tail cuff system (Visitech Systems, Apex, NC). After treatment with the tested compounds of ApoE-deficient and eNOS-deficient mice, blood pressure was compared with the results obtained with placebo treatment.

B. Inhibition of neointimal iateroaenesis (femoral artery cuff)

After 3 days of treatment of ApoE-deficient mice with the appropriate compound (10 mg/kg, pressed in food), the animals are anesthetized with an intraperitoneal injection of pentobarbital (60 mg/kg), followed by an intramuscular injection of xylazine (2 mg/kg), and a cuff is placed around the femoral artery, as described by Moroi et al (J. Clin. Invest, 1998, 101. 1225). Briefly, the left femoral artery is opened. A 2-mm non-occlusive polyethylene cuff, made from PE-50 polyethylene tubing (inner diameter 0.56 mm, outer diameter 0.965 mm, Becton Dickinson, Mountain View, Ca), is placed around the artery and secured with two 7-0 sutures. The right femoral artery is isolated from the surrounding tissue, but the cuff is not placed. Treatment with the appropriate compound is continued for 14 days after surgery. Then the animals are sacrificed. The aorta is taken to determine the release of vascular eNOS by the method of quantitative VVestem blotting. Both femoral arteries are removed, fixed in formalin and embedded in paraffin. 20 transverse sections (10 pm) are cut from the left femoral artery, the part with the cuff, and from the corresponding segment of the right artery. These sections are subjected to standard hematoxylin and eosin staining. Morphometric analyzes were performed using a computer image analysis program (LeicaQWin, Leica Imaging Systems, Cambridge, GB). Neointima and media are determined for each cross-sectional area of the lumen. At the same time, the neointima is defined by the surface between the lumen and the internal elastic layer, and the media is defined by the surface between the internal and external elastic layer. The ratio between the surface of the neointima and the surface of the media is expressed as the neointima/media ratio. The results obtained in the compound group are compared with those obtained in the placebo group.

C. The probability of atherosclerotic hair formation in chronic treatment

ApoE-deficient mice are treated for 16 weeks with the corresponding compound injected into the food, and finally sacrificed. Aortas were removed from each mouse, fixed in formalin and embedded in paraffin. Plaque formation is measured by the formation of lipid lesions in the aorta (from the aortic arch to the diaphragm), and analyzed by staining with red oil O. In this experiment, the quantitative effect of the corresponding compound on the vascular secretion of eNOS in the femoral arteries is determined. The results obtained in the group treated with the compounds are compared with those obtained in the placebo group.

D. Improvement of coronary function in diseased ApoE-deficient mice

Old male C57BL/6J wild-type mice (Charles River Wig GmbH, Sulzfeld) and ApoE-deficient mice (C57BL/6J backgorund, Jackson Laboratory, Bar Harbor, ME) aged 6 months and weighing 28 to 36 g are used in the experiments. Mice were divided into 3 groups (C57BL/6, n = 8; ApoE control, n = 8; ApoE with corresponding compound, n = 8) and received either standard rodent chow (containing 4% fat and 0.001% cholesterol) or standard rodent chow + corresponding compound (30 mg/kg/d, p.o.) for 8 weeks. Mice are anesthetized with sodium pentabarbitone (100 mg/kg, Lp.), and the hearts are immediately removed and placed in perfusion buffer, cooled in ice. A cannula is placed in the aorta and connected to a perfusion machine (Hugo Sachs Electronics, Freiburg, Germany), which is started immediately, with a constant perfusion pressure of 80 mbar (60 mm Hg). Hearts are retrogradely perfused with modified Krebs bicarbonate buffer, balanced with 95% O 2 and 5% CO 2 , and maintained at 37.5°C.

A bevelled small tube (PE50) is passed through the pulmonary vein into the left ventricle and through the ventricular wall, secured at its tip with a grooved end, and connected to the tip of a micromanometer (Millar 1.4 French). Through the same pulmonary vein, a cannula was inserted into the left atrium, and the heart was switched to working mode using a constant ventricular pressure of 13 mbar (10 mm Hg) and a ventricular ejection pressure of 80 mbar (60 mm Hg). Aortic outflow and ventricular inflow are measured using ultrasound probes (HSE/Transonic Systems Inc.). Coronary flow is calculated as the difference between ventricular flow and arterial flow. All hemodynamic data are digitized with a sampling rate of 1000 Hz and registered with a PC, using specialized software (HEM, Notocord).

The hearts are allowed to stabilize for 30 min. During the stationary state, as well as volume and pressure supply, all hemodynamic data are measured. Left ventricular function curves are constructed by varying ventricular pressure. For ventricular curve data acquisition, arterial pressure is set to 80 mbar and ventricular pressure is adjusted in 7 mbar (5 mm Hg) steps over a range of 7 to 35 mbar (5 to 25 mm Hg). Hearts are allowed to stabilize to baseline conditions between pressure and volume feeds.

Claims (10)

1. Compound of formula I, in any of its stereoisomeric forms or mixtures thereof in any ratio, or a pharmaceutically acceptable salt thereof, indicated that in formula I: ring A containing two carbon atoms common to ring A and the cycloalkenyl ring of formula I, represents an aromatic 5-membered or 6-membered ring containing 1 or 2 nitrogen atoms as ring heteroatoms, or an aromatic 5-membered ring containing 1 heteroatom in the ring, which is an oxygen atom or a sulfur atom, or 2 heteroatoms in the ring, one of which is a nitrogen atom and the other is an oxygen atom or a sulfur atom; R<1> and R<4> independently of each other, are selected from the group consisting of: H; unsubstituted or at least monosubstituted Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, the substituents of which are selected from the group consisting of F, OH, Ci-Cs-Alkoxy, Ci-Cs-alkylmercapto, -CN, COOR<6>, CONR<7>R<8> and unsubstituted or at least monosubstituted phenyl and heteroaryl, where the substituents are phenyl and the heteroaryl group is selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3; unsubstituted or at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, d-Cs-alkoxy and CF3; COR<9>;CONR10R11;COOR<12>;CF3; halogen; -CN; NR<13>R<14>; OR<15>; S(0)mR<16>; SO2NR<17>R<18>and NO2; but they cannot be halogen, -CN or NO2, if R<1> or R<4> are attached to a nitrogen atom in the ring; R<2> and R<3> independently of each other, are selected from the group consisting of: H; halogen, -CN; unsubstituted or at least monosubstituted Ci-Cio-alkyl, whose substituents are selected from the group consisting of OH, phenyl and heteroaryl; OH; C 1 -C 10 -Alkoxy; phenoxy; S(0)mR<19>; CF3; - CN; N02; C 1 -C 6 -alkylamino; di(C 1 -C 10 -alkyl)amino; (C 1 -C 6 -alkyl)-CONH-; unsubstituted and at least monosubstituted phenyl-CONH- and phenyl-SO2-0-, whose substituents are selected from the group consisting of halogen, -CN, methyl and methoxy; C1-C6-alkyl-SO2-O-; unsubstituted or at least monosubstituted (Ci-C6-alkyl)-CO-, whose substituents are selected from the group consisting of F, di(Ci-C3-alkyl)amino, pyrrolidinyl and piperidinyl; and phenyl-CO-, where the phenyl part is unsubstituted or at least monosubstituted with substituents selected from the group consisting of C1-C3-alkyl, halogen and methoxy; but they cannot be halogen, -CN or NO2, if R<2> and R<3> are attached to a nitrogen atom in the ring; where if A represents a 6-membered aromatic ring, the present 2 or 3 groups R1, R<2>, R<3> and R<4> are attached to the carbon atoms in the A ring, which are not shared with the cycloalkenyl ring, and if A represents a 5-membered aromatic ring, the present 1, 2 or 3 groups R<1>, R<2>, R<3> and R<4> are present linking the carbon atoms in the A ring, which are not shared with a cycloalkenyl ring, and in the case of a pyrrole, pyrazole or imidazole ring, for nitrogen atom 1 in the ring; R<5> is an Ar or Hetar group, both unsubstituted or bearing one or more identical or different substituents selected from the group consisting of: halogen; -CN; NH2; unsubstituted or at least monosubstituted Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cio-alkoxy, Ci-Cio-alkylamino and di(Ci-C-io-alkyl)amino, whose substituents are selected from the group consisting of F, OH, Ci-C8-alkoxy, aryloxy, Ci-C8-alkylmercapto, NH2, Ci-Ce-alkylamino and di(C 1 -C 8 -allyl)amino; C3-C5-alkanediyl; phenyl; heteroaryl; C1-C4-alkyl substituted with aryl or substituted with heteroaryl; CF3; N02; OH; phenoxy; benzyloxy; (C 1 -C 10 -alkyl)-COO-; S(0)mR<20>; SH; phenylamino; benzylamino; (C1C10-alkyl)-CONH-; (C1C10-alkyl)-CO-N(C1-C4-alkyl)-; phenyl-CONH-; phenyl-CO-N(C1C4-alkyl)-; heteroaryl-CONH-; heteroaryl-CO-N(C1-C4-alkyl)-; (C 1 -C 10 -alkyl)-CO-; phenyl-CO-; heteroaryl-CO-; CF3-CO-; -OCH20-; -OCF20-; -0CH2CH20-; -CH2CH20-; COOR<21>; CONR<22>R<23>;C(NH)-NH2; SOzNR^R<25>;R<26>SO2NH-; R<27>SO2N(C1C6-alkyl)-; and the remainder of a saturated or at least monosaturated aliphatic, monocyclic 5-membered to 7-membered heterocycle, containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, the heterocycle which may be substituted with one or more substituents selected from the group consisting of halogen, d-C3-alkyl, C1-C3-alkoxy, OH, oxo and CF3, where said heterocycle may optionally being fused with said Ar group or said Hetar group; where all aryl, heteroaryl, phenyl, aryl-containing groups, heteroaryl-containing groups, and phenyl-containing groups, which are optionally present in said substituents of said Ar group or said Hetar group, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, CrC3-alkyl, OH, d-C3-Alkoxy and CF3; R<6> is selected from the group consisting of: H; C 1 -C 8 -alkyl, which may be substituted with one or more substituents selected from the group consisting of F, C 1 -C 8 -alkyl and di(C 1 -C 8 -alkyl)amino; aryl-(Ci-C4-alkyl)- and heteroaryl-(Ci-C4-alkyl)-, both of which may be substituted with one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and di(C1-C6-alkyl)amino; R<7> is selected from the group consisting of: H; C 1 -C 8 -alkyl, which may be substituted with one or more substituents selected from the group consisting of F, C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino and phenyl; phenyl; indanyl and heteroaryl; where each of these aromatic groups may be unsubstituted or bear one or more substituents selected from the group consisting of halogen, -CN, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and CF 3 ; R<8> is H or C1-C6-alkyl; R<9> is selected from the group consisting of: C1-C10-alkyl which may be substituted with one or more substituents from the group consisting of F, d-C4- alkoxy and di(C1-C3-alkyl)amino; and unsubstituted or at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of Ci-C3-alkyl, Ci-C3-alkoxy, halogen, -CN and CF3; R<10> independently of R<7> is defined as R<7>; R<11> independently of R<8> is defined as R<8>; R<12> independently of R<6> is defined as R<6>; R<13> is selected from the group consisting of: H; C 1 -C 6 -alkyl; unsubstituted or substituted phenyl, benzyl, heteroaryl, (CrC6-alkyl)-CO-, phenyl-CO- and heteroaryl-CO-, the substituents of which are selected from the group consisting of halogen, -CN, C1-Cr-alkyl, d-C3-alkoxy and CF3; where one or more of these substituents may be present; R<14> independently of R<13>, is defined as R<13>; R15 is selected from the group consisting of: H; C 1 -C 10 -alkyl; (Ci-C3-Alkoxy)-Ci-C3-alkyl- and substituted and unsubstituted benzyl, phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, Ci-C3-alkyl, Ci-C3-Alkoxy and CF3; where one or more of these substituents may be present; R16 is also selected from the group consisting of: Ci-Cio-alkyl, which may be substituted with one or more substituents selected from the group consisting of F, OH, Ci-Cs-alkoxy, aryloxy, Ci-Cs-alkylmercapto, Ci-Ce-alkylamino and di(Ci-C8-alkyl)amino; CF3i substituted or unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-Oralkyl, C1-C3-Alkoxy and CF3; where one or more of these substituents may be present; R17 independently of R<7> is defined as R<7>; R18 independently of R<8> is defined as R<8>; R<19> independently of R<16> is defined as R<16>; R2<0> independently of R<16> is defined as R<16>; R<21>independently of R<6>, is defined as R<6>; R22<z>independently of R<7>, is defined as R<7>; R<23> independently of R<8>, is defined as R<8>; R<24> independently of R<7>, is defined as R<7>; R25 independently of <z>of R<8>, is defined as R<8>; R<26> independently of R<16>, is defined as R<16>; R<27> independently of R<16>, is defined as R<16>; heteroaryl is a 5-membered to 10-membered aromatic, monocyclic or bicyclic heterocycle residue containing one or more heteroatoms selected from the group consisting of N, O and S; A heter group is the residue of a 5-membered to 10-membered, aromatic, monocyclic or bicyclic heterocycle containing one or more heteroatoms selected from the group consisting of N, O and S; aryl is phenyl, naphth-1-yl or naphth-2-yl; The Ar group is phenyl, naphth-1-yl or naphth-2-yl; m is 0, 1 or 2; n is 1, 2 or 3; provided that compounds with the formulas are excluded: wherein R<50> is selected from: hydrogen, unsubstituted C1-C6-alkyl, C1-C6-alkoxy, unsubstituted C1-C6-alkylthio, halogen, -CN, CF3, OH, amino, C1-C6-alkylamino and di(C1-C6-alkyl)amino; and conclude compounds with formulas: in which R<5>1, R52, R53 and R<54> are selected from: hydrogen, unsubstituted or hydroxy-substituted C1-C6-alkyl, halogen, amino, C1-C6-alkylamino and di(C1-C6-alkyl)amino, and R56 is unsubstituted or substituted phenyl, thienyl, furyl, pyrrolyl or oxazolyl; and the compound: N-(2-amino-5,6,7,8-tetrahydro-4-hydroxyquinazolin-6-yl)-3,4-dichlorobenzamide is excluded. 2. The compound of formula I, defined in Claim 1, in any of its stereoisomeric forms or their mixtures in any form, or their pharmaceutically acceptable salts, characterized in that the A ring in formula I represents an aromatic 6-membered ring containing 1 or 2 nitrogen atoms, as heteroatoms in the ring. 3. The compound of formula I, defined in Claim 1, in any of its stereoisomeric forms or their mixtures in any form, or their pharmaceutically acceptable salts, characterized in that the A ring in formula I represents an aromatic 5-membered ring containing a sulfur atom as a heteroatom in the ring, or a sulfur atom and a nitrogen atom as heteroatoms in the ring. 4. The compound of formula I, defined in one or more of Claims 1 to 3, in any of its stereoisomeric forms or their mixtures in any form, or their pharmaceutically acceptable salts, characterized in that the number n in formula I is equal to 1. 5. The compound of formula I, defined in one or more of Claims 1 to 3, in any of its stereoisomeric forms or their mixtures in any form, or their pharmaceutically acceptable salts, characterized in that the number n in formula I is equal to 3. 6. The compound of formula I, defined in one or more of Claims 1 to 5, in any of its stereoisomeric forms or their mixtures in any form, or their pharmaceutically acceptable salts, characterized in that the residues R<1> and R<4> in formula I, independently of each other, are selected from the group consisting of H, Ci-C4-alkyl and halogen, and the residues R<2> and R<3>, independently of each other, are selected from the group consisting of H, C 1 -C 4 -alkyl and halogen. 7. Use of a compound of formula I, defined in one or more of Claims 1 to 6, in any of its stereoisomeric forms or mixtures thereof in any form, or pharmaceutically acceptable salts thereof, as a pharmaceutical product. 8. Pharmaceutical preparation, characterized in that it contains an effective dose of at least one compound of formula I, defined in one or more Claims 1 to 6, in any of its stereoisomeric forms or their mixtures in any form, or their pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. 9. Use of compounds of formula I, in any of its stereoisomeric forms or mixtures thereof in any ratio, or a pharmaceutically acceptable salt thereof, wherein in formula I: ring A containing two carbon atoms in common with ring A and the cycloalkenyl ring of formula I is an aromatic 5-membered or 6-membered ring containing 1 or 2 nitrogen atoms as ring heteroatoms, or an aromatic 5-membered ring containing 1 ring heteroatom, which is an oxygen atom or an atom of sulfur, or 2 heteroatoms in the ring, one of which is a nitrogen atom and the other is an oxygen atom or a sulfur atom; R1 and R<4> independently of each other, are selected from the group consisting of: H; unsubstituted or at least monosubstituted Ci-Cio-alkyl, C2-Cio-alkenyl, C2-C10-alkynyl, the substituents of which are selected from the group consisting of F, OH, d-Cs-alkoxy, Ci-Cs-alkylmercapto, -CN, COOR<6>, CONR<7>R<8> and unsubstituted or at least monosubstituted phenyl and heteroaryl, where the substituents are phenyl and the heteroaryl group is selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3; unsubstituted or at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkoxy and CF3; COR<9>;CONR10R11;COOR<12>; CF3; halogen; - CN; NR<13>R14;OR1<5>; S(0)mR<16>; SO2NR17R18 and NO2; but they cannot be halogen, -CN or NO2, if R<1> or R<4> are attached to a nitrogen atom in the ring; R<2> and R<3> independently of each other, are selected from the group consisting of: H; halogen, -CN; unsubstituted or at least monosubstituted Ci-Cio-alkyl, whose substituents are selected from the group consisting of OH, phenyl and heteroaryl; OH; C 1 -C 10 -Alkoxy; phenoxy; S(0)mR<19>;CF3; -CN; N02; C 1 -C 10 -alkylamino; di(C 1 -C 10 -alkyl)amino; (C 1 -C 6 -alkyl)-CONH-; unsubstituted and at least monosubstituted phenyl-CONH- and phenyl-SO2-0-, whose substituents are selected from the group consisting of halogen, -CN, methyl and methoxy; C1-C6-alkyl-SO2-O-; unsubstituted or at least monosubstituted (Ci-C6-alkyl)-C0-, whose substituents are selected from the group consisting of F, di(Ci-C3-alkyl)amino, pyrrolidinyl and piperidinyl; and phenyl-CO-, where the phenyl part is unsubstituted or at least monosubstituted with substituents selected from the group consisting of C1-C3-alkyl, halogen and methoxy; but cannot be halogen, -CN or NO2, if R<2> and R<3> are attached to a nitrogen atom in the ring, where if A represents a 6-membered aromatic ring, 2 or 3 groups R<1> are present, R<2>, R<3> and R<4> are attached to carbon atoms in the A ring, which are not shared with a cycloalkenyl ring, and if A is a 5-membered aromatic ring, 1, 2 or 3 groups R<1>, R<2>, R<3> and R<4> are attached to carbon atoms in the A ring, which are not shared with the cycloalkenyl ring, and in the case of a pyrrole, pyrazole or imidazole ring, to nitrogen atom 1 in the ring; R<5> is an Ar or Hetar group, both unsubstituted or bearing one or more identical or different substituents selected from the group consisting of: halogen; -CN; NH2; unsubstituted or at least monosubstituted Ci-Cio-alkyl, C2-Cio-alkenyl, C2-Cio-alkynyl, Ci-Cio-alkoxy, Ci-Cio-alkylamino and di(Ci-Cio-alkyl)amino, the substituents of which are selected from the group consisting of F, OH, Ci-Cs-alkoxy, aryloxy, Ci-C8-alkylmercapto, NH2, Ci-C8-alkylamino and di(C 1 -C 5 -allyl)amino; C3-C5-alkanediyl; phenyl; heteroaryl; C1-C4-alkyl substituted with aryl or substituted with heteroaryl; CF3; N02; OH; phenoxy; benzyloxy; (C 1 -C 10 -alkyl)-COO-; S(0)mR<20>; SH; phenylamino; benzylamino; (C1-C10-alkyl)-CONH-; (C 1 -C 10 -alkyl)-CO-N(C 1 -C 4 -alkyl)-; phenyl-CONH-; phenyl-CO-N(d-C4-alkyl)-; heteroaryl-CONH-; heteroaryl-CO-N(C1-C4-alkyl)-; (C 1 -C 10 -alkyl)-CO-; phenyl-CO-; heteroaryl-CO-; CF3-CO-; -OCH20-; -OCF20-; -OCH2CH2O-; -CH2CH2O-; COOR<21>; CONR^R23; C(NH)-NH2; SO2NR<24>R<25>;R<26>SO2NH-; R<27>SO2N(C1-C6-alkyl)-; and the remainder of a saturated or at least monosaturated aliphatic, monocyclic 5-membered to 7-membered heterocycle, containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, the heterocycle which may be substituted with one or more substituents selected from the group consisting of halogen, Ci-C3-alkyl, Ci-C3-alkoxy, OH, oxo and CF3, where said heterocycle may optionally being fused with said Ar group or said Hetar group; where all aryl, heteroaryl, phenyl, aryl-containing groups, heteroaryl-containing groups and phenyl-containing groups, which are optionally present in said substituents of said Ar group or said Hetar group, may be substituted with one or more substituents selected from the group consisting of halogen, -CN, Ci-C3-alkyl, OH, Ci-C3-Alkoxy and CF3; R<6> is selected from the group consisting of: H; C1-C6-alkyl, which may be substituted with one or more substituents selected from the group consisting of F, C1-C8-alkoxy and di(C1-C8-alkyl)amino; aryl-(C 1 -C 4 -alkyl)- and heteroaryl-(C 1 -C 4 -alkyl)-, both of which may be substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 -alkyl, d -C 4 -alkoxy and di(C 1 -C 6 -alkyl)amino; R<7> is selected from the group consisting of: H; C 1 -C 8 -alkyl, which may be substituted with one or more substituents selected from the group consisting of F, C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino and phenyl; phenyl; indanyl and heteroaryl; where each of these aromatic groups may be unsubstituted or bear one or more substituents selected from the group consisting of halogen, -CN, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and CF 3 ; R<8> is H or C1-C6-alkyl; R<9> is selected from the group consisting of: C1-C10-alkyl which may be substituted with one or more substituents from the group consisting of F, C1-C4-alkoxy and di(C1-C3-alkyl)amino; and unsubstituted or at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of Ci-C3-alkyl, Ci-C3-alkoxy, halogen, -CN and CF3; R<10>independently of R<7>, is defined as R<7>;R<11>independently of R<8>, is defined as R<8>;R<12>independently of R<6>, is defined as R<6>; R<13> is selected from the group consisting of: H; C 1 -C 6 -alkyl; unsubstituted or substituted phenyl, benzyl, heteroaryl, (Ci-C6-alkyl)-CO-, phenyl-CO- and heteroaryl-CO-, the substituents of which are selected from the group consisting of halogen, -CN, Ci-C3-alkyl, Ci-C3-alkoxy and CF3; where one or more of these substituents may be present; R<14> independently of R<13>, is defined as R<13>; R15 is selected from the group consisting of: H, Ci-Cio-alkyl; (Ci-C3-Alkoxy)-Ci-C3-alkyl- and substituted and unsubstituted benzyl, phenyl and heteroaryl, whose substituents are selected from the group consisting of halogen, -CN, C1-C3alkyl, C1-C5-Alkoxy and CF3; where one or more of these substituents may be present; R<16> is selected from the group consisting of: Ci-Cio-alkyl, which can be substituted with one or more substituents selected from the group consisting of F, OH, C-i-Ce- alkoxy, aryloxy, Ci-Cs-alkylmercapto, Ci-Cs-alkylamino and di(Ci-C8-alkyl)amino; CF3i substituted or unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C6- alkoxy and CF3; where one or more of these substituents may be present; R17 independently of R<7> is defined as R<7>; R<18> independently of R<8> is defined as R<8>; R<19> independently of R<16> is defined as R<16>; R<20> independently of R<16>, is defined as R<16>; R<21>independently of R<6>, is defined as R<6>;R<22>independently of R<7>, is defined as R<7>;R23>independently of R<8>, is defined as R<8>;R<24>independently of R<7>, is defined as R<7>;R<25>independently of R<8>, is defined as R<8>; R<26> independently of R<16>, is defined as R<16>; R<27> independently of R<16>, is defined as R<16>; heteroaryl is a 5-membered to 10-membered aromatic, monocyclic or bicyclic heterocycle residue containing one or more heteroatoms selected from the group consisting of N, O and S; A heter group is the residue of a 5-membered to 10-membered, aromatic, monocyclic or bicyclic heterocycle containing one or more heteroatoms selected from the group consisting of N, O and S; aryl is phenyl, naphth-1-yl or naphth-2-yl; "Ar group is phenyl, naphth-1-yl or naphth-2-yl; m is 0, 1 or 2; n is 1,2 or 3; for the manufacture of a medicament for stimulating the secretion of endothelial NO synthase. 10. The use of the compound of formula I, defined in Claim 9, in any of its stereoisomeric forms or mixtures thereof in any ratio, or their pharmaceutically acceptable salts, for the production of medicaments for the treatment of cardiovascular diseases, stable and unstable angina pectoris, coronary heart disease, Prinzmetal's angina, acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusion disease, endothelial dysfunction, atherosclerosis, restenosis, endothelial damage after PTCA, hypertension, essential hypertension, pulmonary hypertension and secondary hypertension, renovascular hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes, complications from diabetes, nephropathy, retinopathy, angiogenesis, bronchial asthma, chronic renal disorders, cirrhosis of the liver, osteoporosis, the manifestation of limited memory or limited learning ability, or to reduce cardiovascular risk in women in post-menopause and in women taking contraceptives.